Epitope-based therapeutic targets in HCV genotype 1 non-structural proteins: a novel strategy to combat emerging drug resistance.

IF 4.6 2区医学 Q2 IMMUNOLOGY

Frontiers in Cellular and Infection Microbiology Pub Date : 2024-11-07 eCollection Date: 2024-01-01 DOI:10.3389/fcimb.2024.1480987

Mireayi Tudi, Adili Sawuti, Maimaitituerhong Abudurusuli, Chao Wu, Xiaoyu Chen, Gulimire Ailimu, Kuerbannisa Wulayin, Maimaitiaili Tuerxun

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引用次数: 0

Abstract

Introduction: The hepatitis C virus (HCV) poses a major global health challenge, with its non-structural proteins being essential for viral replication and pathogenesis. Mutations in these proteins significantly contribute to drug resistance, necessitating innovative therapeutic strategies. This study aims to identify epitope-based therapeutic targets in the non-structural proteins of HCV genotype 1, employing in-depth in silico tools to counteract emerging drug resistance.

Methods: We retrieved approximately 250 sequences of each non-structural protein from the NCBI database, capturing a broad spectrum of variability and sequence alignments, variability analysis and physicochemical property analysis were conducted. We utilized the TEPITOOL server by IEDB to predict cytotoxic T lymphocyte (CTL) epitopes. Following this, we assessed the efficiency of TAP transport and proteasomal cleavage using IEDB's combined predictor tool. The epitopes were selected based on conservancy analysis, immunogenicity, allergenicity, and presence in non-glycosylated regions, ensuring high predictive scores and suitability as vaccine candidates. Epitopes were docked with the HLA-A*02:01 allele and Toll-like receptor-3 using the ClusPro server. The immune response potential of the epitopes was evaluated through in-silico immune stimulation.

Results: The study identified 27 potential CTL epitopes from the non-structural proteins, including NS3, NS4a, NS4b, NS5a, and NS5b. Out of these, three lead epitopes demonstrated high conservation (>90%), strong binding affinities to HLA-A*02:01 and TLR-3, and robust immune response potential. These epitopes also showed favorable characteristics such as being non-allergenic and non-glycosylated.

Conclusion: This comprehensive in-silico analysis provides a promising foundation for developing an epitope-based vaccine targeting HCV non-structural proteins, offering a novel approach to overcoming drug resistance in HCV treatment.

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基于表位的 HCV 基因 1 型非结构蛋白治疗靶点：对抗新出现的耐药性的新策略。

导言：丙型肝炎病毒（HCV）对全球健康构成重大挑战，其非结构蛋白对病毒复制和致病至关重要。这些蛋白的突变在很大程度上导致了耐药性，因此需要创新的治疗策略。本研究旨在确定 HCV 基因 1 型非结构蛋白中基于表位的治疗靶点，利用深入的硅学工具来对抗新出现的耐药性：我们从 NCBI 数据库中检索了每个非结构蛋白的约 250 个序列，捕获了广泛的变异性，并进行了序列比对、变异性分析和理化性质分析。我们利用 IEDB 的 TEPITOOL 服务器预测细胞毒性 T 淋巴细胞（CTL）表位。随后，我们利用 IEDB 的组合预测工具评估了 TAP 转运和蛋白酶体裂解的效率。表位的选择基于保守性分析、免疫原性、过敏原性和非糖基化区域的存在，以确保高预测分数和作为候选疫苗的适宜性。利用 ClusPro 服务器将表位与 HLA-A*02:01 等位基因和 Toll 样受体-3 进行了对接。通过体内免疫刺激评估了表位的免疫反应潜力：结果：该研究从包括 NS3、NS4a、NS4b、NS5a 和 NS5b 在内的非结构蛋白中发现了 27 个潜在的 CTL 表位。在这些表位中，有三个表位的保存率很高（大于90%），与HLA-A*02:01和TLR-3的结合亲和力很强，具有很强的免疫应答潜力。这些表位还显示出非过敏性和非糖基化等有利特征：这项全面的分子内分析为开发以HCV非结构蛋白为靶标的表位疫苗奠定了良好的基础，为克服HCV治疗中的耐药性提供了一种新方法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Frontiers in Cellular and Infection Microbiology IMMUNOLOGY-MICROBIOLOGY

CiteScore

7.90

自引率

7.00%

发文量

1817

审稿时长

14 weeks

期刊介绍： Frontiers in Cellular and Infection Microbiology is a leading specialty journal, publishing rigorously peer-reviewed research across all pathogenic microorganisms and their interaction with their hosts. Chief Editor Yousef Abu Kwaik, University of Louisville is supported by an outstanding Editorial Board of international experts. This multidisciplinary open-access journal is at the forefront of disseminating and communicating scientific knowledge and impactful discoveries to researchers, academics, clinicians and the public worldwide. Frontiers in Cellular and Infection Microbiology includes research on bacteria, fungi, parasites, viruses, endosymbionts, prions and all microbial pathogens as well as the microbiota and its effect on health and disease in various hosts. The research approaches include molecular microbiology, cellular microbiology, gene regulation, proteomics, signal transduction, pathogenic evolution, genomics, structural biology, and virulence factors as well as model hosts. Areas of research to counteract infectious agents by the host include the host innate and adaptive immune responses as well as metabolic restrictions to various pathogenic microorganisms, vaccine design and development against various pathogenic microorganisms, and the mechanisms of antibiotic resistance and its countermeasures.