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DRUG REPURPOSING : a REVIEW

Yesenia Harris

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About Authors1AGARWAL POONAM*, 2RATHORE KAMAL SINGH, VIJAY KAVITA21Department of Pharmaceutics, Bhupal Nobles’ College of Pharmacy Udaipur, Rajasthan,2Faculty, Jaipur, College of Pharmacy, Jaipur India, 313001.
Email : charmiagarwal823@gmail.com

ABSTRACT
The Covid-19 pandemic has brought detrimental impact for the human and economic costs, majorly due to the lack of specific treatment. At this stage, drug repurposing is the better option to arrive at treatments of covid-19 in short-term instead of complementary to immunotherapy. Currently, most of the examples of drug repurposing can be seen that are undertaken in clinical trials for the potential Covid-19 treatments. Food Drug Administration (FDA) approved a repurposed antiviral drug i.e. remdesivir in October 2019, as the first treatment of covid-19. It will cover different prospects of repurposing which are undergoing non-clinical and clinical trials or with some level of evidence that are emerging from clinical studies are overviewed.In this review article will provide deep understanding about several emergence of drugs which are going to repurposed for dealing with covid-19 situation. We will discuss about real case studies whereas existing drugs are using to treat patients with covid-19 by executing drug repurposing strategy.In last, we will highlight some commercial and intellectual barriers to drug repurposing and strategies in order to facilitate equitable access for incoming therapeutic solution.

INTRODUCTION
The new and highly contagious severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) is the major reason of outbreak which triggered novel coronavirus disease, covid-19 as resulted it represents a pandemic threat to worldwide health. More than 65 million confirmed cases along with 1.5 million deaths worldwide received yet that results in economic losses and unprecedented human (1,2). Currently, there is no treatment option available which can help to get rid-off from the deadly contagious disease, Covid-19. However, scientific communities and international politics have already retorteddynamically to offer new therapeutic and diagnostic solutions. Regulatory agencies across globe have executed fast-track process to acceleratethe development and marketing authorization of the diagnostic and therapeutic solutions against coronavirus disease. For example, The US-FDA has introduced a special emergency program to advance the development of coronavirus therapies as the Coronavirus Treatment Acceleration Program (CTAP) (3). This website (CTAP) lists more than 560 drug development programs in the planning stage, above 370 trials have reviewed by the agency. There are five covid-19 treatments that are authorized for the emergency use (encompassing, very recently, one treatment (remdesivir) and anti-arthritis drug barcitinib, have approved by FDA against Covid-19. Though, there are various international collaborativedrug development initiatives arose to give instant responses to the current crisisi.e. crowd sourcing, private-public association, open innovation among other models (4), (5). Our experts may highlight small molecule and immunotherapies, encompassing hyperimmune globulin, monoclonal antibodies and convalescentplasma transfusion among emerging treatments against Covid-19 (6), (7).In fact, significant focus has placed on the therapeutic interventions that have provided a solution such as vaccines in the short-mid-term.It is not quite shocking that so far only approved drug therapy. Most of the researchers are undergoing or underwent clinical trials for the repurposed drug.

SIGNIFICANCE OF DRUG REPURPOSING
Drug purposing is considered emerging strategy wherein existing or available drugs, already have been done clinical trials and tested safe in humans, are re-organized against difficult diseases.To implement drug repurposing strategy, there is a reason such as, we all know very well, outbreak of covid-19/20has brought worst result economic loss, poor global public health. However, all efforts must be made towards prevention of 2019/2020 outbreak.Average cost of the de novo development stated around $1 billion USD. To combat with sever acute respiratory syndrome coronavirus 2 (SARS-CoV-2) takes a snapshot look towards drug repurposing strategy which is also known as drug repositioning or reprofiling (8). These strategy promises to determine antiviral agents for the Covid-19 disease in a critical time. Remdesivir has received as conditional marketing authorization from the European Commission because they investigated that this drug contains antiviral molecule (9). This drug is effective for the treatment of covid-19 in adults and teenagerswith pneumonia who needs supplemental oxygen. Even, no other treatments have been approved to date.In past few years, there are lots of pharmaceutical companies which are developing new drugs with the discovery of novel biological targets by implementing repositioning strategy in the drug discovery and development program(8), (10). This strategy is considered highly efficient, low-cost, time-saving and minimum risk of failure.

To find new molecular entities (NME) through traditional approach or de-nova drug discovery process is quite lengthy, expensive and time consuming. Drug repurposing is a lot like recycling and has become one of the cheaper and most fasted way to bring treatment in the market, especially for those who survives with rare and ultra-rare diseases. This drug repurposing strategy has been gained substantial momentum lately, around one out of three approvals links to drug repurposing in recent years.While repurposed therapeutics currently generates around 25% revenue of the pharmaceutical industry(11). So, most of the pharmaceutical companies has been progressively integrated this approach into the life cycle management of the pharmaceutical products (11) (12). Previous knowledge on the proposed repurposed researchers, such as manufacturing data and pharmacokinetic assists shorten the long drug development timeline. It diminishes cost of the development as well. The potential advantage of the drug repurposing is to prove safety of the repurposing researchers, which are less likely to fail at initial clinical trials or may bypass Phase 1 trials if the drug compatibility with the original is met (12), (13)).

World Health Organization proposed a document on Draft Target Product Profiles (TPP) that is based on the treatment of Covid-19. With this proposed document, organization highlightspreferred profiles which are majorly to be instantly fulfilled through repurposed drugs(14), for instance:
1. Small children and pregnant women are involved in the target population.
2. Safety profile superior or similar to existing therapeutic agents.
3. Absence of adverse events or detrimental events that needs to be monitoring.
4. Efficiency to rapid scaling up at different costs per dose that enable broad use.

There are number of things that considered relative advantageous of drug repurposing (comparison with de novo drug discovery). Currently, so many ongoing covid-19 project as well as clinical trials emphasizes on repurposed matter (15). The reason behind is that it is essential to address urgent therapeutic needs for the orphan diseases in a cost and time efficient manner. Researchers are putting more efforts on discriminating virus-focused treatments from host-based treatment.

Virus and Host Focused drug repurposing (13, 15)
Immunoprophylaxis (vaccines) can be defined as the priming for activation of host immune response against particular pathogens. It is considered one of the safest approaches among others to control or eradicate various virus diseases (i.e. influenza virus, hepatitis virus, measles, papillomavirus). In the early 80s’HIV was considered global pandemic, caused by the human immunodeficiency virus, which advanced modern antiviral drug development. To date, the development of antiviral therapies has become centred on chronic viral diseases i.e. Hepatitis C virus (HCV) and HIV, which are the major reason for 68% of the FDA antiviral drug approvals (16). In contrast, only fewer drugs come in market authorization to treat sever acute respiratory diseases. Currently repositioning strategy is majorly focused against SARS-CoV-2 in exploring the cross-reactivityof biological and chemical entities, with the particular immunomodulating agents(16), (17). For example, first actions, involving clinical trials, were proposed to test the therapeutic efficacy of antiviral drugs targeting viral RNA replication (i.e. Remdesivir) (20) and protease (i.e. ritonavir, lopinavir (17)). While adjunctive treatment is completely based on monoclonal antibodies (i.e. tocilizumab (21) or drugs (i.e. dexamethasone (27), chloroquine (22)), have aimed to diminish inflammatory responses which already have been assayed in covid-19 patients. Ivermectin is also one of the great examplesof a host-directed agent that explored for its potential in order to hampering SARS-CoV-2 replication. FDA also has approved macrocyclic lactone drug for the treatment of several parasitic diseases,because this drug is belonging from broad spectrum category and its antiviral activity has been linked with the resistance of the host nuclear transport importin. However, this is hijacked by the viruses by suppressing the antiviral responses or to translocate viral protein which are essential for replication. The pharmacological dose of Ivermectin (23)may impart anti-SARS-CoV-2 activity. Even many of drugs, alone or in combination, were or currently subjected of clinical evaluation. Globe’s largest trials of covid-19 therapies have been executed among existing drugs remdesivir, lopinavir/ritonavir, hydroxychloroquine combination but results were highly disappointed. Last October, FDA permittedIV remdesivir for the treatment of covid-19 in adults and adolescent from 12 years of age who requires supplemental oxygen.

Recent surveying study analysing IFNa in Covid-19 patients linkedearly administration of the cytokine along with decreased mortality and its late use along with high mortality or delayed recovery (24). Thus, there are some other examples, based on them researchers are focusing on drug repositioning research against Covid-19 Wirth novel and steady finding on the pathophysiology of SARS-CoV-2 infection (26).

New intervention in drug repurposing strategy
Currently, most of the researchers are doing study on existing drugs so that they can repurposed drug to combat with current pandemic. Recently, a scientist Achal Agarwal and HOD & CEO, NK Agarwal of Memorial Chemistry Research Lab, Macsen Drugs, Udaipur have quoted that Methylene Blue (a 120-year-old drugs), is repurposed for Covid-19 treatment.

Methylene Blue

o IUPAC Name: 3,7 bis (dimethylamino)-phenothiazin-5-ium chloride
o Molecular Formula: C16H18N3SCl
o Molecular Weight: 319.86 g/mol
o This is also known as MethylthionineChloride. It is a Planar Tricyclic heteroaromatic diamino phenothiazine compound.
o It was firstly synthesized by Heinrich Caro in 1876 and started to be used as an antimalarial from since 1800s. Methylene Blue is considered as the Globe’s first Synthetic Drug.
o It is used as an antimalarial at the end of World War II.
o Antiseptic properties is are also posses’ by methylene Blue.
o In 1930s, it was started to being used for the treatment of Methemoglobinemia which is still worldwide approved to deal with Methemoglobinemia.
o However, methylene blue is given in combination to inactivate the viral load (inactivate broad spectrum of viruses encompassing HIV viruses, Hepatitis viruses etc.) in blood plasma before transfusion.

Pharmacological Properties of Methylene Blue :
o Methylene Blue contains a broad-spectrumAntiviral Action with or without presence of light by different mechanismsi.e. Interaction b/w the RNA pairs, Protein binding, Singlet Oxygen generation etc.
o Methylene Blue decreases oxidative stress and scavenges Reactive oxygen species as well as oxidative free radicalscaused by its antioxidant property.

Methylene Blue as an available drug for various indications, worldwide :
o Methylene Blue injection approved worldwide as first-in-line treatment of Methemoglobinemia.
o Methylene Blue Injection has achieved a ‘Grandfathered Drug’ profile in USA as a pre-1938 drug. Methylene Blue has long history of safety and use so it is titled as a ‘Grandfathered Drugs’ which do not require any type of FDA approvals in United State.
o This drug is available in different forms and using in number of countries till now i.e. URIBEL & UROGESIC BLUE Capsules (contains 10mg Methylene Blue) in US as Urinary antiseptic,DOMITAZOL (OTC Drug, contains 25mg Methylene Blue) in Vietnam as Urinary Septic, Methylene Blue MMX tablets (contains 200mg of Methylene Blue)approved in Europe in 2020 August for visualization of colorectal lesion while Colonscopies, UROLENE BLUE (65mg Methylene Blue tablets) is another effective Grandfathered Drugs in US to diagnose urinary septic, CYSTEX as OTC drug (contains 20mg Methylene Blue USP and other ingredients) in Brazil as urinary antiseptic.
o Methylene Blue IV is pretty known for the treatment of Cytokinin Release Syndrome, Vasoplegia Syndrome etc.

Known Safe Dosages of Methylene Blue in numerous routes of Administration and Indications :
o Methylene Blue can be given by Intravenous route as Methemoglobinemia. The safe dosage of this drug can be given up to 2 mg/ Kg in short single dose is considered safest. This information is collected by USFDA Medical Review of Provayblue NDA: 204630 (29).
o It can be administered orally as Colonoscopy. The safest dosage is up to 400mg (single dose) that data gathered from an article: Methylene blue MMX(R) tablets for chromo endoscopy. DOI: 10.1016/j.cct.2011.11.006 (30).
o It is also administered orally as antimalarial drug. The safest single dose of this drug is about 500mg. This statement is quoted by Ingeborg Walter-Sack, et.al, DOI: 10.1007/s00228-008-0563-x (31).

Contraindication of Methylene Blue
o Methylene Blue never administered to patients who having history of G6PD (Glucose 6 Phosphate) deficiency. The reason behind is that it can develop haemolysis in G6PD patients.
o Pregnant women and lactating women should not be administered this drug.

Discussion and Result
Antiviral Activity of Methylene Blue in Covid-19 infection
Invitro Study 1
“Methylene Blue has capability to inhibit the SARS-CoV-2 Spike-ACE2 Protein-Protein interaction. It is a mechanism of action of Methylene Blue that can play prime role in its Antiviral Activity against Covid-19”.This claim is done by experts Damir Bojadzic, Oscar Alcazar, Peter Buchwald in Diabetes Research Institute, University of Miami, FL, United States (27).
Key findings of invitro study:
o Methylene Blue represented a low micromolar half maximal inhibitory concentration (IC50) around 3?M in the Assay of ELISA-based Protein Binding.
o While in an assay of SARS-CoV-2 spikes pseudoviral entry into ACE2 imparting HEK293T cells, Methylene Blue showed a low micromolar half maximal inhibitory concentration (IC50) around 3.5?M in the form of a concentration dependent manner (32).Conclusion
Based on the above discussion can be concluded that Methylene Blue can effectively inhibit protein-2 interaction b/w SARS-CoV-2 Spike protein at low micromolar concentration. It can inhibit viral entry of SARS-CoV-2 spikes bearing pseudovirus into ACE2 expressing cells by normal clinical dosage around 200 mg (TID, Oral).

Invitro Study 2 (32)
“Methylene Blue resits the replication of SARS-CoV-2 in vitro” statement illustrated by Mathieu Gendrot, Julien Andreani, Isabelle Duflot et.al 2020 in International Journals of Antimicrobial Agents (2020).
Key Findings:
o Methylene Blue has capability to inhibit replication of SARS-CoV-2.
o It shows cytotoxic concentration (CC50) of > 100 ?M in Vero E6 cells.
o Invitro antiviral activity of Methylene Blue (0.75 ?M) was found more higher as compared other drugs i.e. azithromycin (20.1 ?M), remdesivir (23 ?M), ritonavir (>100 ?M) or lopinavir (26.6 ?M).
Conclusion
Based on the above discussion it is summarized that methylene blue can inhibit (90% inhibition) the SARS-CoV-2 virus. Antiviral activity of Methylene Blue is higher as compared other currently used drugs.

Proposed Route of Administration of Methylene Blue in Covid-19 patients (33) :
Methylene Blue administers intravenously in mild to moderate Covid-19 patients which demonstrated good response in controlling the infection.This drug in severe Covid-19 patients have also shown reduced morality rates.
Methylene Blue Inj. 1% USP is existing in Ampules of 10 mL (10 mg/ml, 100 mg in one ampule).
Following process is followed for the administration:
o Administer 100 mg to an adult patient by IV in 20-30 minutes.
o Later 4-5 hours give an IV infusion of 15-18 mg per hour.
o Administer drug total 200 mg within 24 hours.
o Repeat this drug for three days.
Currently, Phase1, Phase IIand Phase III clinical trials of methylene blue have been done in covid-19 patients and achieved results are desirable. Recently, Dr. Rajesh Dere, who is the in-charge of BKC Jumbo COVID centre, Mumbai has gained breakthrough results in treating serious Covid-19 patients by using 120-year-olddrug Methylene Blue Injection. Around 120 patients with severe Covid-19 were admitted in ICU who were administered the drug Methylene Blue intravenously. Administration of this drug has brought desirable results in the BKC Covid Centre, Mumbai.

CONCLUSION
This article has been concluded about significance of repurposing drug and causes for executing this strategy.In this article it has summarized that how experts at different centres are putting efforts to make existing drugs in to repurposed manner. Virus and host focused drug repurposing term has also explained in it which stated that how available drugs alone or with combination are using to deal with globally covid-19 pandemic. There are number of drugs i.e. remdesivir, dexamethasone, chloroquine, hydro-chloroquine, combination of interferon and cytokinin, ivermectin etc. used to treat severe Covid-19/20 pandemic in which remdesivir was approved by number of regulatory authorities to treat covid-19 patients. However, above mentioned drugs were used in the form of repurposed drug. Methylene Blue is the new intervention of repurposed drug which is evident by experts to have potential to treat severe patient with Covid-19 because it has much antiviral action rather than other drugs like remdesivir. Invitro case studies first and second, finding and their conclusion has been concluded in this article. Pharmacological actions, route of administration and existing applications have been concluded in it. With the support of invitro study 1 and invitro study 2, it has illustrated that Methylene Blue is a Repurposable Drugs against SARS-CoV-2. The Viral inhibition of this drug is much better than Remdesivir in both type SARS-CoV-2 strains. Drug repurposing strategy is proving quite time and cost-effective in this peak period.

REFERENCES
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2. Nicola M, Alsafi Z, Sohrabi C, et al. (2020); the socio-economic implications of the coronavirus pandemic (COVID-19): A review. Int J Surg.; 78:185-193.
3. Food and Drug Administration. Coronavirus Treatment Acceleration Program (CTAP). [Accessed on October 10th 2021]. Available from: https://www.fda.gov/drugs/coronavirus-covid-19-drugs/coronavirus-treatment-acceleration-program-ctap.
4. Chodera J, Lee AA, London N, et al. (2020);Crowdsourcing drug discovery for pandemics. Nat Chem. 12:581.
5. Chesbrough H. (2020); to recover faster from Covid-19, open up: managerial implications from an open innovation perspective. Ind Mark Manag. 88:410-413.
6. Islam MT, Nasiruddin M, Khan IN, et al. Perspective on emerging therapeutic interventions for COVID-19. Front Public Health. 2020; 8:281.
7. Sarkar C, Mondal M, Islam MT, (2020); Potential therapeutic options for COVID-19: current status, challenges, and future perspectives. Front Pharmacol. 11. DOI:10.3389/fphar.2020.572870.
8. Ashburn TT, Thor KB (2004); Drug repositioning: identifying and developing new uses for existing drugs. Nat Rev Drug Discov 3: 673-683.
9. Cao, Y. C., Deng, Q. X., & Dai, S. X. (2020); Remdesivir for severe acute respiratory syndrome coronavirus 2 causing COVID-19: An evaluation of the evidence. Travel Medicine and Infectious Disease. 101647. https://doi.org/10.1016/j.tmaid.2020.101647.
10. Cha, Y., Erez, T., Reynolds, I.J., Kumar, D., Ross, J., Koytiger, G., Kusko, R., Zeskind, B., Risso, S., Kagan, E., Papapetropoulos, S., Grossman, I., Laifenfeld, D. (2018); Drug repurposing from the perspective of pharmaceutical companies. British Journal of Pharmacology, 175(2), 168-180. https://doi.org/10.1111/bph.13798.
11. Naylor S, Kauppi DM, Schonfeld JP (2015); Therapeutic drug repurposing, repositioning and rescue part II: business review. Drug Discovery World. 16(2):57-72.
12. Naylor S, Kauppi DM, Schonfeld JP (2015); Therapeutic drug repurposing, repositioning and rescue: part III: market exclusivity using intellectual property and regulatory pathways. Drug Discovery World. 16(3):62-69.
13. Oprea TI, Overington JP (2015); Computational and practical aspects of drug repositioning. Assay Drug Dev Technol. 13(6):299-306.
14. World Health Organization. WHO target product profiles for COVID-19 therapeutics. (2020); [cited October 10th 2020]. Available from: https://www.who.int/publications/m/item/who-target-product-profiles-for-covid-19-therapeutics.
15. Chaudhuri S, Symons JA, Deval J.(2018); Innovation and trends in the development and approval of antiviral medicines: 1987-2017 and beyond. Antiviral Res. l; 155:76-88.
16. Forum of International Respiratory Societies (2017); The global impact of respiratory disease. Second ed. Sheffield: European Respiratory Society.
17. Hung IF, Lung KC, Tso EY, et al.(2020); Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial. Lancet. 395:1695-1704.
18. Pushpakom S, Iorio F, Eyers PA, (2019); Drug repurposing: progress, challenges and recommendations. Nat Rev Drug Discov. 18:41- 58.
19. Beigel, J. H., Tomashek, K. M., Dodd, L. E., Mehta, A. K., Zingman, B. S., Kalil, A. C., et al. (2020); Remdesivir for the treatment of covid-19 — preliminary report. N. Engl. J. Med. [Epub ahead of print].
20. Campochiaro, C., Della-Torre, E., Cavalli, G., De Luca, G., Ripa, M., Boffini, N., et al. (2020); Efficacy and safety of tocilizumab in severe COVID-19 patients: a single-centre retrospective cohort study. Eur. J. Intern. Med. 76, 43-49.
21. Maskin LP, Olarte GL, Jr PF, (2020); High dose dexamethasone treatment for Acute respiratory distress syndrome secondary to COVID-19: a structured summary of a study protocol for a randomised controlled trial. Trials. 21:743.
22. Cha, Y., Erez, T., Reynolds, I. J., Kumar, D., Ross, J., Koytiger, G. Laifenfeld, D. (2017); Drug repurposing from the perspective of pharmaceutical companies. British Journal of Pharmacology, 175(2), 168-180.
23. Caly L, Druce JD, Catton MG, (2020); The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 3:104787.
24. Wang N, Zhan Y, Zhu L, (2020); Retrospective multicentre cohort study shows early interferon therapy is associated with favourable clinical responses in COVID-19 patients. Cell Host Microbe. 28:455-464.
25. Singh TU, Parida S, Lingaraju MC, (2020); Drug repurposing approach to fight COVID-19. Pharmacol Rep. 72:1479-1508.
26. Gautret P, Lagier JC, Parola P, (2020); Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 56:105949.
27. Talevi A, Bellera CL (2020); Challenges and opportunities with drug repurposing: finding strategies to find alternative uses of therapeutics. Expert Opin Drug Discov. 15:397-401.
28. USFDA Medical Review of Provayblue NDA: 204630, 2016. (https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/204630Orig1_toc.cfm).
29. Repici, A., Di Stefano, A. F. D., Radicioni, M. M., Jas, V., Moro, L., & Danese, S. (2012); Methylene blue MMX(R) tablets for chromoendoscopy. Safety tolerability and bioavailability in healthy volunteers. Contemporary Clinical Trials, 33(2), 260-267.
30. Walter-Sack, I., Rengelshausen, J., Oberwittler, H., Burhenne, J., Mueller, O., Meissner, P., & Mikus, G. (2008); High absolute bioavailability of methylene blue given as an aqueous oral formulation. European Journal of Clinical Pharmacology, 65(2), 179-189.
31. Mathieu Gendrot, Julien Andreani,(2020); Methylene blue inhibits the replication of SARS-Cov-2 in vitro, International Journal of Antimicrobial Agents.
32. Bojadzic D, Alcazar O, Buchwald P. Methylene Blue inhibitsinvitro the SARS-CoV-2 Spike – ACE2 Protein-Protein Interaction a Mechanism That Can Contribute to Its Antiviral Activity against COVID-19. bioRxiv [Preprint] 2020; [cited 2020 October 21]. Available from https://doi.org/10.1101/2020.08.29.273441.Available at [https://www.frontiersin.org/articles/10.3389/fphar.2020.600372/full].

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Kokum Butter in Cosmetics

Yesenia Harris

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Vinay Kumar Singh.
Head-Formulation
Kumar Organic Products Research Centre Pvt. Ltd.,
Bengaluru
Email : formulation_krc@kopresearchcentre.net

Plant-derived oils and butters are among the most popular ingredients for a variety of personal care products including Cream, lotions, Lipstick, lip balm, Make- ups and hair treatments.

The mere mention of kokum brings to mind the small, round, red to purple-hued fruits, relished in curries for their sour flavour, besides being sipped on as a delightful sharbat and chilled juice. While the kokum fruits, scientifically termed Garcinia indica and native to the Western Ghats region of Maharashtra, Karnataka, Goa, are extensively used in cooking traditional Indian dishes, the flattened, black, pliable seeds within yield a rather beneficial substance too, an inherently oily element known as kokum butter and this plant-based matter derived from the kernels of kokum, a crop belonging to the same botanical family as mangosteen, confers astounding merits for glowing skin and silky hair. Kokum fruit is an inseparable part of Konkani cuisine.

Kokum butter is an oleaginous material isolated from the seeds of the kokum fruit. Each raw or ripe kokum fruit contains about 5 to 10 large black seeds, which are separated from the pulp. They are then wiped clean to remove all dirt and debris, squeezed under high pressure and subsequently processed as vegetable oil to obtain kokum butter, otherwise known as kokum oil.

Kokum butter possesses a firm texture and usually appears in shades of light grey, pale white, creamy yellow. It is in fact a hard edible butter at room temperature, used as a substitute for cocoa butter in preparing confectioneries, as well as for topical use on skin and hair. Nevertheless, owing to its ease of melting upon touching the skin and umpteen valuable phytochemical compounds, kokum butter is widely incorporated into commercial personal care products.

Kokum Butter is high in essential saturated fatty acids like Omega 6 and Omega 3 which prevent regularly skin damage by making Skin Healthier and Balancing Moisture in the skin.
Unrefined Kokum butter provides the skin with extreme hydration and moisturization. It consists of a high Anti-inflammatory property that helps to reduce inflamed skin and issues like allergies, infections, rashes, and irritation. Kokum Butter is also enriched with Antioxidants and Vitamin E which helps to immune the skin against free radicals and toxins.

The moisturizing agent in the Raw and Pure Kokum butter prevents the skin from dehydrating and promotes skin cell regeneration. It also combats the visible signs of aging by preventing issues like decoloration, fine lines, and wrinkles. Kokum butter not only Benefits Skin Health but can also boost the Health of the Immune System and cell functioning.

Whipped Kokum Butter is proven to be beneficial for hair by promoting Hair Growth. It locks the moisture deep into the skin and nourishes the itchy & dry scalp and also reduces Dandruff & Hair Fall. Organic and unrefined Kokum butter is an ideal ingredient for lip balms, lip gloss, lotions, moisturizers, and ointments because of the presence of rich emollients in it.

Kokum butter is Non-comedogenic so it does not clog pores or cause acne. You can also use whipped Kokum butter for eczema and acne scars. When it is applied on a regular basis the skin will automatically soften and restore its elasticity. The shelf life of Kokum butter is quite long as compared to any other body butter because of the high oxidative stability.
The advantages of kokum butter include :
o No scent. Kokum butter naturally has no scent. Cocoa, coconut, and shea butters are well known for their distinctive fragrances. Forperson sensitive it fragrance, kokum butter may be a better option.
o Easily absorbed. Unlike most other plant butters, kokum butter is remarkably light, absorbed quickly and easily, and not greasy.
o Doesn’t clog pores. U-nlike shea butter, kokum butter won’t clog your pores or cause acne.
o Very structurally stable. Kokum butter is one of the most structurally and chemically stable plant butters available. It works great as a natural emulsifier or hardening agent for homemade cosmetics.

Benefits of Kokum Butter for Skin and Hair
Kokum seeds contain vitamin E and many powerful antioxidants. These nutrients strengthen the immune system and cell function, and help reverse the damage caused by free radicals.1. Skin
It’s no surprise that kokum butter is the ingredient makeup artists often use. This ingredient is loved for its highly nourishing properties. It helps create a smooth texture on the skin. This omega-rich butter can be applied directly on lips, hands, knees, and elbows. Following are benefits Kokum butter has for skin.
o Improves skin cell regeneration
This ingredient is also known for regenerating skin cells. At the same time, it effectively reverses skin cell degeneration, and thus prevents damage even before it occurs. It is a natural emollient, and can thus go to the deepest layers of the epidermis. This helps to heal wounds and chapped skin.
o Reduces visible signs of aging
It is also believed that this buttery ingredient helps address and prevent multiple skin aging signs. These include hyperpigmentation, increased fragility, thinning of the skin, reduced elasticity, dehydration, and dark spots. It also helps create a protective moisture barrier against pollution and seasonal changes.
o Deeply Moisturizes dry skin
It is best known for its ability to be an intense moisturizing agent. It can be used to restore the skin’s moisture content, including your lips, feet, hands, etc. Unlike other kinds of butter used in skin care, kokum oil or butter is not sticky.
It is lightweight, gets easily absorbed, and leaves no signs of greasiness after application. This is why most skincare experts advise it for people with sensitive skin.
o Treats acne
This butter has a strong moisturizing ability and is considered non-comedogenic, which means it does not clog pores. It restores moisture content to dry or irritated skin.
o Reduces skin inflammation
It can help ward off signs of inflammation on the skin regardless of the cause. It also prevents the risk of future inflammation by safeguarding the skin against skin aggressors.
o Best for sensitive skin
Known for its healing and anti-inflammatory properties, this naturally-occurring emollient makes the best alternative for sensitive skin. If your skin is sensitive to most skin care products, this ingredient is gentler and easily tolerated by the skin. So, even people with sensitive skin can use kokum butter for skin lightening and brightening.

2. Hair
This nourishing butter is equally helpful in hair care too. Below are some of the most important ways in which this natural butter helps hair.
o Anti-dandruff solution
There are common hair care issues like itchy or flaky scalp, hair loss, and other concerns. Its anti-inflammatory properties help reduce infection and inflammation on the scalp.
It also keeps the scalp moisturized. This is crucial while preventing dandruff and seasonal dryness, and thus creating a healthy scalp environment.
o Natural hair conditioner
Kokum butter is saturated with omega-3 fatty acids and other vital moisturizing agents that give the hair the right amount of hydration. It moisturizes the scalp and prevents oxidative stress in the hair cuticles.
o Stimulates hair growth
This butter is popularly known to stimulate hair growth. This natural plant butter is a perfect remedy for thick and long hair. It is rich in antioxidants, fatty acids, and lauric acid content. The fatty acids nourish the scalp and form a protective barrier against environmental or seasonal changes.

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Lack of Medicines in Greece and the Solution of Generics

Yesenia Harris

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The problem of drug shortages is taking on alarming proportions worldwide. In Greece at the moment, antibiotics, antipyretics and inhaled medicines are in main shortage, but Greek pharmacists noted that more than 200 drugs for almost the entire spectrum of diseases were in permanent shortage.

The Causes
It is noted that 60-80% of the products used in medicines are produced in China and India. Their production has fallen by 60% due to a new outbreak of the coronavirus in China resulting in limited exports. Another reason is the war in Ukraine delaying distributions main reason for drug shortages. Unfortunately, Europe has chosen to depend to a significant extent on China and India in the field of pharmaceutical raw materials. According to high-ranking officials in the sector, the objective of the European Commission is to “move” production from Asian countries to Europe, in order to facilitate the supply of medicines within the continent. Of course, in this particular period of time, with inflation soaring, and the energy crisis exponentially increasing the cost of drug production, a feeling of insecurity is being cultivated as to whether Europe will be able to respond to a new wave of shortages of even more important drugs.

Another cause according to pharmacists, is the ever-increasing parallel exports. That’s because certain medicines can give up to 15 times more profit to the pharmaceutical warehouse if it is available abroad than in a pharmacy in the Greek market. The National Pharmaceutical Organization of Greece (EOF) decided to put a brake on the parallel exports of a large category of medicines for which there are shortages in the Greek market. In addition to the previous measures, the Greek Minister of Health asked the warehouses to immediately declare the stocks they have of the elliptical drugs and they must make them available without delay to the Greek market.

Nevertheless, reports claim that of the drugs whose export was banned on November 22, 80% of them have identical generics, so there is no public health issue.

?he solution that consumers refuse due to unawareness
Generic medications are a class of medication that, while lacking the brand name, are identical to brand-name products in terms of dosage, strength, administration method, quality, and intended use. They are frequently accessible after the original drug’s patent has expired, enabling other pharmaceutical companies to create and market less expensive versions of the drug. The primary motivation behind the development of generic medications is to lower the cost of healthcare. The pharmaceutical business that created the new medicine received a patent for it. This patent grants the corporation the sole right to market the medication for a specified period of time. Because there are no other options during this time, the manufacturer can charge a premium price for the drug. When the patent on the drug expires, other businesses may begin making and marketing generic versions of it. Because the firms making these generic versions do not have to invest in the research and development that went into manufacturing the original drug, they are often far less expensive than their brand-name counterparts. Drugs sold under generic names are as secure and efficient. They function similarly to the original medication and have the same active components. Generic medications must go through extensive testing to guarantee that they are identical to the brand-name medication in terms of quality, safety, and effectiveness. While using generic medications can help reduce the cost of healthcare, there are some instances where the brand-name choice may be chosen.

For instance, if a patient has previously experienced a negative reaction to a generic version of a medication, their doctor may advise that they take the brand-name version to prevent any prospective problems. Finally, we understand that if consumers are made aware of what generics are and of the controls that must be submitted to be released on the market, in periods of shortages we will not face such a serious issue in treatments.

Georgios-Marios Bolmpasis
MPharm Student University of Athens
Vice President of Pharmacy Students Association(Athens)
Member of European Pharmaceutical Students Association
Member of Greek Pharmaceutical Students Federation

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Computational Analysis of HCV Entry Inhibitors for Hepatitis C Treatment – a Molecular Docking Approach

Yesenia Harris

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About Author: Karthika M
Postgraduate in Bioinformatics
Bharathiar Universitym.karthika1@gmail.com

ABSTRACT
Hepatitis C virus (HCV) is a major human pathogen associated with life-threatening liver disease, affect 170 million people worldwide. Hepatitis C virus (HCV) envelope proteins mediate the entry of virus into cells by binding to cellular receptors, resulting in fusion of the viral membrane with the host cell membrane and permitting the viral genome to enter the cytoplasm. Entry inhibitors would inhibit the viral entry itself.
Envelope protein E2, responsible for viral entry taken as target is modeled using Modeller 9.10. 47 small molecules have been taken for docking with envelope protein.10 small molecules have been selected for Induced Fit Docking based on the Glide energy, Docking Score.
Ligand 20 is showing good binding affinity towards the target in active site, having Docking Score -6.07, Glide Energy -60.41, IC50 value 1.5 and it obeys Lipinski’s Rule of Five. ADMET Properties were also studied for these compounds. All computational works are performed in the Schrodinger suite 2009. Hence the present study suggests that the ligand 20 with further in vitro and in vivo testing can be introduced as an effective inhibitor against HCV for development of curative therapy against Hepatitis C.

REFERENCE ID: PHARMATUTOR-ART-1650

INTRODUCTIONHepatitis C is a contagious liver disease that results from infection with hepatitis C virus (HCV). The infection is often asymptomatic, but chronic infection can lead to scarring of the liver and ultimately to liver cirrhosis. In some cases, those with cirrhosis will go on to develop liver failure, liver cancer or life-threatening esophageal and gastric varices. HCV is transmitted through contact with the blood of an infected person. (Jou, Muir, 2008)

The Hepatitis C virus persists in the liver in about 85% of those infected. This persistent infection can be treated with medication; peginterferon and ribavirin are the current standard therapy. Overall, between 50-80% of people treated are cured. Those who develop cirrhosis or liver cancer may require a liver transplant. Hepatitis C is the leading cause of liver transplantation though the virus usually recurs after transplantation. No vaccine against hepatitis C is currently available.(Ghany MG et al.,2009)

Hepatitis C virus(HCV)
Hepatitis C virus (HCV) is a small (55-65 nm in size), enveloped, positive-sense single-stranded RNA virus of the family Flaviviridae. Hepatitis C virus is the cause of hepatitis C in humans.(Kapoor et al.,2011)

Structure

Fig : Structure of Hepatitis C Virus

The hepatitis C virus particle consists of a core of genetic material (RNA), surrounded by an icosahedral protective shell of protein, and further encased in a lipid (fatty) envelope of cellular origin. Two viral envelope glycoproteins, E1 and E2, are embedded in the lipid envelope.

Genome

Fig: HCV Genome

HCV Envelope Protein as a Target
Cellular processes, such as clathrin-mediated endocytosis or endosome formation, are probably not very clean targets, and agents designed to target those processes would be likely to have severe adverse effects. Agents that bind host factors may interfere with normal cellular functions, resulting in an unacceptable adverse effect profile. Agents that bind viral components in the entry process, such as the HCV envelope proteins, might be more likely to be selected as target.

Entry Inhibitors
Entry inhibitors may be particularly helpful after liver transplantation, where universal reinfection of the graft often results in rapid fibrosis progression and subsequent graft failure. Even therapies transiently inhibiting HCV cell entry could prevent graft reinfection and thus greatly improve the effectiveness of liver transplantation.

MATERIALS AND METHODS

Molecular Modelling
This procedure, also termed Comparative Modelling or knowledge based modelling developed a three-dimensional model from a protein sequence (target) based on the structures of homologous proteins (Templates).

Modeller
Modeller is a computer program that model three-dimensional structures of proteins and their assemblies by satisfaction of spatial restraints.

The user provided an alignment of a sequence to be modeled with known related structures and Modeller automatically calculated a model containing all non-hydrogen atoms.More generally, the input to the program was restraints on the spatial structure of the amino acid sequence and ligands to be modeled. The output was a 3D structure that satisfied these restraints as well as possible. A 3D model was obtained by optimization of a molecular Probability Density Function (PDF). The molecular PDF for comparative modeling was optimized with the variable target function procedure in Cartesian space that employed methods of conjugate gradients and molecular dynamics with simulated annealing.

Searching for Structures
First, it was necessary to put the target sequence into the PIR format readable by Modeller.

A search for potentially related sequences of known structure could be performed by the profile.build() command of MODELLER.

Selecting a Template
To select the most appropriate template for the query sequence over the similar structures, we would use thealignment.compare_structures() command to assess the structural and sequential similarity between the possible templates.

Model Building
Once a target-template alignment was constructed, MODELLER calculated a 3D model of the target completely automatically, using its automodel class. The following script would generate five similar models of HCV E2 based on the template structure and the alignment file “align_HCV.ali”. The most important output files were ‘model-single-log’, which reported warnings, errors and other useful information including the input restraints used for modeling that remain violated in the final model, which contained the coordinates of the five produced models, in the PDB format.

Model Evaluation
If several models were calculated for the same target, the ‘best’ model could be selected by picking the model with the lowest value of the MODELLER objective function. The DOPE potential in MODELLER was used to evaluate the model fold.

Molecular Docking
The computational process of searching for a ligand that is able to fit both geometrically and energetically to the binding site of a protein is called molecular docking.

Docking Analysis using MAESTRO
Maestro is the graphical user interface for all of Schrodinger’s products like CombiGlideTM, EpikTM, GlideTM, ImpactTM, LiaisonTM, LigprepTM,MacroModelTM,PhaseTM, PrimeTM, QikPropTM, QsiteTM, and StrikeTM. It contains tools for building, displaying, and manipulating chemical structures for organizing, loading and storing these structures and associated data, and for setting up, monitoring, and visualizing the results of calculations on these structures.

Docking Method – GLIDE(Grid Based Ligand Docking with Energitics)
Glide searches for favorable interactions between one or more typically small ligand molecules and a typically larger receptor molecule usually a protein. Each ligand must be a single molecule, while the receptor may include more than one molecule such as a protein and a cofactor. GLIDE can be run in rigid or flexible docking modes and it the later automatically generates conformation for each input ligand. The combination of positions and orientation of the ligand relative to the receptor along with its conformation in flexible docking is referred to as a ligand pose.

Protein Preparation
A typical PDB structure file consists only of heavy atoms. Therefore, hydrogen does have to be added prior to use in Glide calculations, which use an all-atom force field.

The protein preparation facility consists of two components, preparation and refinement. After ensuring chemical correctness, the preparation component adds hydrogen and neutralizes side chains that are not close to the binding cavity and do not participate in salt bridges. The refinement component performs a restrained impact minimization of the co-crystallized complex, which reorients side-chain hydroxyl groups and alleviates potential steric clashes.

Ligand Preparation
Glide also allows importing the lead molecule in SDF, mol or mol2 format which is drawn using chemsketch software. These determined structures are minimized using two methods
1. Ligprep Minimization
2. Impact Minimization

Ligprep generate tautomers and conformers for single ligand and Impact minimization uses two algorithms for minimization steepest descent and conjugate gradient which runs for 500 to 1000 cycles. Both methods use OPLS force field for minimizing the structures.

Receptor Grid Generation
The ligand should be selected for the ligand to identify the active site to bind with the protein.

If the protein structure in PDB is not complexed with ligand, then the active site of the protein should be specified. We can particularly specify the residues or can specify the region.

Ligand Docking
For docking the ligand with the target protein the receptor grid file should be specified and the ligprep out file should be selected.

Designing of Inhibitors
Novel class of HCV Rimcazole derivatives were recently reported for their anti-HCV activity and they were designed using MARVINSKETCH and PYMOL. Totally 47 Rimcazole derivatives were modeled using MarvinSketch software.

Collection of protein
Protein is retrieved from PDB (protein data bank) based on the lowest resolution. To model the protein, the template structure is selected (PDB id : 2xfc) from PDB.

Modelled Structure of HCV E2

Protein Information

Length

862 Residues

Target Sequence

Uniprot ID – Q99IB8

Template

Chikungunya Virus Envelope Protein E2 PDB ID – 2XFC

Active Site Residues

Lys 373, Asn 409, Trp 414, Asp 417, Glu 418, Leu 705, Tyr 706, Asp707, Ser 708, Ser 710, Thr 712, Val 714.

RESULTS

Ramachandran Plot for HCV E2 Glycoprotein

Docking Result

Compounds

Docking Score

Glide Energy(kcal/mole)

20

-4.01

-51.50

19

-5.32

-49.91

34

-5.35

-49.75

6

-5.51

-49.72

7

-4.8

-49.65

4

-6.24

-48.84

3

-6.24

-48.84

5

-6.24

-48.84

30

-4.49

-48.28

27

-3.92

-47.32

8

-5.08

-46.68

22

-4.74

-46.56

12

-4.01

-46.55

28

-4.40

-46.28

33

-5.28

-46.20

35

-4.82

-45.55

18

-4.58

-45.39

14

-4.69

-45.21

41

-4.83

-44.95

9

-4.88

-44.63

26

-3.62

-44.62

46

-4.55

-44.51

44

-4.55

-44.51

45

-4.55

-44.51

43

-4.55

-44.51

47

-4.55

-44.51

42

-4.55

-44.51

31

-5.32

-44.21

23

-5.26

-43.89

32

-4.44

-42.59

10

-4.12

-41.70

40

-6.58

-41.40

Induced Fit Docking Results

Ligands

Docking Score

Glide Energy (kcal/mole)

Interaction

Distance (?)

20

-6.07

-60.41

[N-H…O] Tyr367

Lys373[N-H…O]

3.043

2.986

25

-6.84

-56.73

Lys373[N-H…O]

Lys574[N-H…O]

3.017

2.803

30

-8.19

-55.52

Asn409 [N-H…O]

Gln418 [N-H…O]

3.022

2.848

24

-6.08

-54.17

Lys373[N-H…O]

Lys574[N-H…O]

2.918

3.089

34

-7.85

-54.01

[N-H…O] Asp417

Asp417 [N-H…O]

Asn409 [N-H…O]

Trp414 [N-H…O]

3.796

3.130

2.867

2.852

Induced Fit Docking Results of Ligand 20

Poses

Docking Score

Glide Energy (kcal/mole)

Interaction

Distance (?)

1

-6.07

-60.41

[N-H…O] Tyr367

Lys373[N-H…O]

3.043

2.986

2

-5.70

-55.90

Lys373 [N-H…O]

Lys371 [O-H…O]

2.980

3.044

3

-4.26

-54.70

Lys373 [N-H…O]

Lys574 [N-H…O]

[N-H…O] Glu577

2.992

2.802

4

-8.19

-55.52

Asn409 [N-H…O]

Gln418 [N-H…O]

3.022

2.848

5

-6.30

-54.42

[N-H…O] Glu577

Lys574 [N-H…O]

Lys373 [N-H…O]

2.909

3.065

2.732

6

-7.44

-53.27

Gln418 [N-H…O]

2.895

7

-7.62

-53.13

Gln418 [N-H…O]

Asn409 [N-H…O]

2.904

3.214

Interaction of Ligand 20 in PYMOL

Ligplot of Ligand 20

DISCUSSION
The compound 20 is most potent with an IC50 of 1.5 nM because of the presence of methyl ester group in the series of compounds. The methyl ester at the 3-position improved the potency by several fold. The dimethyl sulfonamide compound 15 showed excellent potency with an IC50 of 5 nM. The N-methylated analogue 24 is as potent as compound 20. When compared to the corresponding 4,6-disubstituted-2-amino pyrimidines, aromatic heterocycles/aromatics such as phenyl sulfone (30) or difluoro phenyl sulfonamides (34) are also active but less potent than pyrimidine analogues. Disubstituted 2-amino/2-oxo pyrimidines and dimethyl sulfonamide groups are best for high potency. Based on binding competition and resistance profiles, this compound class appears to be mechanistically similar to ITX 5061.

CONCLUSION
Envelope Protein E2 (Glycoprotein) responsible for HCV Entry is targeted to inhibit the HCV. Both protein and ligands are minimized using OPLS forcefield. From the 47 compounds, 10 compounds were selected for Induced Fit Docking based on Docking Score and Glide Energy. The ligands chosen abides Lipinski’s Rule of Five. These small molecules belong to a distinct chemical class from ITX 5061, first in class drug, currently in Phase Ib Clinical Trial.

Ligand 20 is showing good binding affinity towards the target having Docking Score -6.07 and Glide Energy -60.41 and IC50 value 1.5nM and it binds with the Active site of the target protein. Hence the present study suggests that the ligand 20 with further in vitro and in vivo testing can be introduced as an effective inhibitor against HCV for development of curative therapy against Hepatitis C.

References
1) Kato N (2000). “Genome of human hepatitis C virus (HCV): gene organization, sequence diversity, and variation”. Microb. Comp. Genomics 5 (3): 129-51.
2) Op De Beeck A, Dubuisson J (2003). “Topology of hepatitis C virus envelope glycoproteins”. Rev. Med. Virol. 13 (4): 233-41.
3) F. Habersetzer, A. Fournillier, J. Dubuisson, D. Rosa, S. Abrignani, C. Wychowski, I. Nakano, C. Tr?po, C. Desgranges, G. Inchausp?, Characterization of human monoclonal antibodies speci?c to the hepatitis C virus glycoprotein E2 with in vitro binding neutralization properties, Virology 249 (1998) 32-41.
4) Targeting HCV entry for development of therapeutics. Wong-Staal F, Syder AJ, McKelvy JF.Viruses. 2010 Aug;2(8):1718-33. Epub 2010 Aug 18.
5) Glycosylation of hepatitis C virus envelope proteins. Goffard A, Dubuisson J. CNRS-UPR2511, Institut de Biologie de Lille, Institut Pasteur deLille, Lille, France. Biochimie. 2003Mar-Apr;85(3-4):295-301.
6) Z.Y. Keck, A. Op de Beeck, K.G. Hadlock, J.M. Xia, T.K. Li, J. Dubuisson, S.K.H. Foung, Hepatitis C virus E2 has three immunogenic domains containing conformational epitopes with distinct properties and biological functions, J. Virol. 78 (2004)9224-9232.
7) G. Leroux-Roels, R. DeLeys, L. Stuyver, A.Elewaut, J. Philipp?, I. Desombere, J.Paradijs, G. Maertens, Lymphoproliferative responses to hepatitis C virus core, E1, E2, and NS3 in patients with chronic hepatitis C infection treated with interferon alfa, Hepatology 23 (1996) 8-16.
8) B. Bartosch, J. Dubuisson, F.L. Cosset, Infectious hepatitis C virus pseudo- particles containing functional E1-E2 envelope protein complexes, J. Exper.Med. 197 (2003) 633-642.
9) M. Rodriguez-Rodriguez, D. Tello, B. Yelamos, J. Gomez-Gutierrez, B. Pacheco, S. Ortega, A.G. Serrano, D.L. Peterson, F. Gavilanes, Structural properties of the ectodomain of hepatitis C virus E2 envelope protein, Virus Res. 139 (2009) 91-97.
10) V. Sandrin, P. Boulanger, F. Penin, C. Granier, F.L. Cosset, B. Bartosch, Glycosylation of hepatitis C virus envelope proteins, Biochimie 85 (2003) 295-301.
11) A.OpDe Beeck, L. Cocquerel, J. Dubuisson, Biogenesis of hepatitis C virus glycoproteins, J. Gen. Virol. 86 (2005) 3189-3199.
12) A. Op De Beeck, C. Voisset, B. Bartosch, Y. Ciczora, L. Cocquerel, Z. Keck, S. F. Helle, J. Dubuisson, Hepatitis C virus entry into host cells,Cell Mol. Life Sci. Cell entry of hepatitis C virus, Virology 348 (2006) 1-9.
13) M. Lambot, S. Fretier, A.O. De Beeck, B. Quatannens, S. Lestavel, W. Clavey, J. Bartosch, B.; Dubuisson, J.; Cosset, F.L. Infectious hepatitis C virus pseudo-particles containing functional E1-E2 envelope protein complexes. J. Exp. Med. 2003, 197, 633-642.
14) Bartosch, B.; Dubuisson, J.; Cosset, F.L. Infectious hepatitis C virus pseudo-particles containing functional E1-E2 envelope protein complexes. J. Exp. Med. 2003, 197, 633-642.
15) Bankwitz D., Steinmann E., Bitzegeio J., Ciesek S., Friesland M., Herrmann E., Zeisel M. B., Baumert T. F., Keck Z. Y., et al., Hepatitis C virus hypervariable region 1 modulates receptor interactions, conceals the CD81 binding site, and protects conserved neutralizing epitopes. J Virol 84, 5751-5763.

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