Evaluating Drug Resistant Mutations to HCV NS3 Protease Inhibitors in Iranian Naïve Patients

Abstract

Hepatitis C virus (HCV) is an important causative agent of acute and chronic hepatitis. The non-structural protein 3 (NS3) of HCV retains two enzymatic domains which are essential for the virus life cycle. The serine protease inhibitors have developed to improve the responses of HCV-infected patients that have an effective impact on NS3. Nonetheless, drug-resistant variants are the prominent obstruction toward therapeutic success. Sixty-eight Iranian patients infected with HCV genotypes 1a and 3a and diagnosed with chronic active hepatitis were examined. Plasma viral RNA was used to amplify and sequence the HCV NS3 gene; also, HCV viral load, molecular genotyping, and the ALT test were determined for all samples. The sequencing results were used to be analyzed by several reliable bioinformatics tools to determine the physicochemical properties, B cell epitopes, post-modification changes and secondary/tertiary structures; and evaluate the interactions with four drugs. Our results showed that 45% of patients were 1a genotype, the rest of them belonged to 3a genotype, and 70% of patients had abnormal ALT and AST levels. Several substitutions were observed in codons I52M, S102A, L132I, and S166A in 3a genotype and 40, 153 and 91 in 1a genotype. Interactions between references and sample sequences with available drugs showed that different genotypes or common mutations could not have any striking effect on the energy value of the interaction. This study displayed resistance mutations and genetic polymorphisms of NS3 region that are crucial in determining the efficiency of protease inhibitor class of drugs in Iranian HCV infected patients.

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Abbreviations

HCV:

Hepatitis C virus

NS3:

Non-structural protein 3

HCC:

Hepatocellular carcinoma

IHN:

Iran hepatitis network

NS:

Nonstructural

PIs:

Protease inhibitors

RDRP:

RNA-dependent RNA polymerase

HIV:

Human immunodeficiency virus

HBsAg:

Hepatitis B surface antigen

aa:

Amino acid

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Acknowledgements

The authors would like to thank Shiraz University of Medical Sciences, Shiraz, Iran and Shariati Hospital, Dr. Shahin Merat, professor of gastrology and hepatology at Tehran University of Medical Sciences for providing us with absolute opportunity to be in touch with his patients, also Tehran University of Medical Sciences personnel for sampling, and Center for Development of Clinical Research of Nemazee Hospital and Dr. Nasrin Shokrpour for editorial assistance.

Funding

This study was funded by Shiraz University of Medical Sciences (Grant Number 94-01-01-9218).

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Correspondence to Tayebeh Hashempour or Mohammad Ali Davarpanah.

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Hashempour, T., Dehghani, B., Mousavi, Z. et al. Evaluating Drug Resistant Mutations to HCV NS3 Protease Inhibitors in Iranian Naïve Patients. Int J Pept Res Ther 26, 1699–1710 (2020). https://doi.org/10.1007/s10989-019-09957-6

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Keywords

  • HCV
  • NS3
  • Drug resistance
  • Bioinformatics