Hepatitis C viral infection has become a current cause for concern. In the present article, Feeney and Chung [1] presented a commendable wide view on recent trends on the treatment regimen of HCV. It has been observed that our major concern has been the non-structural proteins. Among other several causes this may be due to their less conformational changes in comparison to the structural proteins during a viral life cycle. Therefore, NS3, NS4A, NS5A and NS5B have been targeted with several inhibitors for quite some time.
Following the philosophy of “prevention is better than cure”, it can be idealized that attempting to avert the viral entry to the host cell may be an equivalent important approach. The efforts reflected in the literature show [2, 3] that we have sufficient understanding about the viral entry mechanism and the role of the glycoproteins (E1 and E2) including their complex interplay with HDL,CD81 for gaining cellular entry.
The mechanism of envelope protein fusion is complex and undergoes conformational and structural changes where alteration occurs from trimer raft formation to monomerization and dimer formation. The monomer structure of Hepatitis C virus envelope protein is represented in Figure 1. But in this whole process the recognition factors for the cellular receptors are almost specific. Therefore, devising strategy for stopping the viral entry may be effective and may have comparatively low risk factors for patients too.
Recent studies in this regard are attempting various alternative approaches. This includes small molecules with considerable efficiency [4]. Some inhibitors were tested against the envelope proteins such as lectin cyanovirin-N (CV-N), celgosivir, n-butyl deoxynojirimycin and N-(n-nonyl) deoxynojirimycin [2,5]. Different types of antibody generation and neutralizing agents [6,7] and DNA aptamers [8] for inhibiting the Hepatitis C viral envelope protein was done successfully in the past.
Although the discussed treatment lines are promising and quite effective in the present context, exploring more options will never go in vain where the envelope protein can be considered[9]. Deceptive viral mutations may survive our treatment strategy at any time. Alternative target search may become cost effective depending on the pharma policies adopted in future. We hope to prevent the disease with greater efficiency in the coming years depending on the ongoing R and D efforts globally.
References:
[1] Feeney ER, Chung RT. Antiviral treatment of hepatitis C. BMJ, 2014; 349 doi: http://dx.doi.org/10.1136/bmj.g3308
[2] Sharma SD. Hepatitis C virus: Molecular biology & current therapeutic options. Indian J Med Res , 2010; pp 17-34.
[3] Op De Beeck A, Cocquerel L, Dubuisson J. Biogenesis of hepatitis C virus envelope glycoproteins. J Gen Virol. 2001; 82( 11):2589-95.
[4] Baldick CJ, Wichroski MJ, Pendri A, Walsh AW, Fang J, Mazzucco CE, Pokornowski KA, Rose RE, Eggers BJ, Hsu M, Zhai W, Zhai G, Gerritz SW, Poss MA, Meanwell NA, Cockett MI, Tenney DJ. A novel small molecule inhibitor of hepatitis C virus entry. PLoS Pathog. 2010;2:6(9):e1001086. doi: 10.1371/journal.ppat.1001086.
[5] Helle F, Wychowski C, Vu-Dac N, Gustafson KR, Voisset C, Dubuisson J. Cyanovirin-N inhibits hepatitis C virus entry by binding to envelope protein glycans. J Biol Chem. 2006; 1:281(35):25177-83. Epub 2006 Jun 29.
[6] Ray R, Meyer K, Banerjee A, Basu A, Coates S, Abrignani S, Houghton M, Frey SE, Belshe RB. Characterization of antibodies induced by vaccination with hepatitis C virus envelope glycoproteins. J Infect Dis. 2010; 5:202(6):862-6. doi: 10.1086/655902.
[7] Giang E, Dorner M, Prentoe JC, Dreux M, Evans MJ, Bukh J, Rice CM, Ploss A, Burton DR, Law M. Human broadly neutralizing antibodies to the envelope glycoprotein complex of hepatitis C virus. Proc Natl Acad Sci U S A. 2012; 17:109(16):6205-10. doi: 10.1073/pnas.1114927109. Epub 2012 Apr 4.
[8] Yang D, Meng X, Yu Q, Xu L, Long Y, Liu B, Fang X, Zhu H. Inhibition of hepatitis C virus infection by DNA aptamer against envelope protein. Antimicrob Agents Chemother. 2013; 57(10):4937-44. doi: 10.1128/AAC.00897-13. Epub 2013 Jul 22.
[9] Jeulin H, Velay A, Murray J, Schvoerer E. Clinical impact of hepatitis B and C virus envelope glycoproteins. World J Gastroenterol. 2013; 7:19(5):654-64. doi: 10.3748/wjg.v19.i5.654.
Competing interests:
No competing interests
22 August 2014
Amit Kumar Banerjee
Research Fellow
Neelima Arora, Past Post Doctoral Fellow
CSIR-Indian Institute of Chemical Technology
Biology Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, Telangana, India
Rapid Response:
Hepatitis C viral infection has become a current cause for concern. In the present article, Feeney and Chung [1] presented a commendable wide view on recent trends on the treatment regimen of HCV. It has been observed that our major concern has been the non-structural proteins. Among other several causes this may be due to their less conformational changes in comparison to the structural proteins during a viral life cycle. Therefore, NS3, NS4A, NS5A and NS5B have been targeted with several inhibitors for quite some time.
Following the philosophy of “prevention is better than cure”, it can be idealized that attempting to avert the viral entry to the host cell may be an equivalent important approach. The efforts reflected in the literature show [2, 3] that we have sufficient understanding about the viral entry mechanism and the role of the glycoproteins (E1 and E2) including their complex interplay with HDL,CD81 for gaining cellular entry.
The mechanism of envelope protein fusion is complex and undergoes conformational and structural changes where alteration occurs from trimer raft formation to monomerization and dimer formation. The monomer structure of Hepatitis C virus envelope protein is represented in Figure 1. But in this whole process the recognition factors for the cellular receptors are almost specific. Therefore, devising strategy for stopping the viral entry may be effective and may have comparatively low risk factors for patients too.
Recent studies in this regard are attempting various alternative approaches. This includes small molecules with considerable efficiency [4]. Some inhibitors were tested against the envelope proteins such as lectin cyanovirin-N (CV-N), celgosivir, n-butyl deoxynojirimycin and N-(n-nonyl) deoxynojirimycin [2,5]. Different types of antibody generation and neutralizing agents [6,7] and DNA aptamers [8] for inhibiting the Hepatitis C viral envelope protein was done successfully in the past.
Although the discussed treatment lines are promising and quite effective in the present context, exploring more options will never go in vain where the envelope protein can be considered[9]. Deceptive viral mutations may survive our treatment strategy at any time. Alternative target search may become cost effective depending on the pharma policies adopted in future. We hope to prevent the disease with greater efficiency in the coming years depending on the ongoing R and D efforts globally.
References:
[1] Feeney ER, Chung RT. Antiviral treatment of hepatitis C. BMJ, 2014; 349 doi: http://dx.doi.org/10.1136/bmj.g3308
[2] Sharma SD. Hepatitis C virus: Molecular biology & current therapeutic options. Indian J Med Res , 2010; pp 17-34.
[3] Op De Beeck A, Cocquerel L, Dubuisson J. Biogenesis of hepatitis C virus envelope glycoproteins. J Gen Virol. 2001; 82( 11):2589-95.
[4] Baldick CJ, Wichroski MJ, Pendri A, Walsh AW, Fang J, Mazzucco CE, Pokornowski KA, Rose RE, Eggers BJ, Hsu M, Zhai W, Zhai G, Gerritz SW, Poss MA, Meanwell NA, Cockett MI, Tenney DJ. A novel small molecule inhibitor of hepatitis C virus entry. PLoS Pathog. 2010;2:6(9):e1001086. doi: 10.1371/journal.ppat.1001086.
[5] Helle F, Wychowski C, Vu-Dac N, Gustafson KR, Voisset C, Dubuisson J. Cyanovirin-N inhibits hepatitis C virus entry by binding to envelope protein glycans. J Biol Chem. 2006; 1:281(35):25177-83. Epub 2006 Jun 29.
[6] Ray R, Meyer K, Banerjee A, Basu A, Coates S, Abrignani S, Houghton M, Frey SE, Belshe RB. Characterization of antibodies induced by vaccination with hepatitis C virus envelope glycoproteins. J Infect Dis. 2010; 5:202(6):862-6. doi: 10.1086/655902.
[7] Giang E, Dorner M, Prentoe JC, Dreux M, Evans MJ, Bukh J, Rice CM, Ploss A, Burton DR, Law M. Human broadly neutralizing antibodies to the envelope glycoprotein complex of hepatitis C virus. Proc Natl Acad Sci U S A. 2012; 17:109(16):6205-10. doi: 10.1073/pnas.1114927109. Epub 2012 Apr 4.
[8] Yang D, Meng X, Yu Q, Xu L, Long Y, Liu B, Fang X, Zhu H. Inhibition of hepatitis C virus infection by DNA aptamer against envelope protein. Antimicrob Agents Chemother. 2013; 57(10):4937-44. doi: 10.1128/AAC.00897-13. Epub 2013 Jul 22.
[9] Jeulin H, Velay A, Murray J, Schvoerer E. Clinical impact of hepatitis B and C virus envelope glycoproteins. World J Gastroenterol. 2013; 7:19(5):654-64. doi: 10.3748/wjg.v19.i5.654.
Competing interests: No competing interests