利用免疫信息学和分子建模综合方法,以 DNA 依赖性 RNA 聚合酶为靶标,研制针对三种重要痘病毒的下一代多价候选疫苗。

IF 4.7 3区 医学 Q1 INFECTIOUS DISEASES Journal of Infection and Public Health Pub Date : 2024-06-07 DOI:10.1016/j.jiph.2024.102470
Anuj Kumar , Mansi Dutt , Budheswar Dehury , Gustavo Sganzerla Martinez , Krishna Pal Singh , David J. Kelvin
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引用次数: 0

摘要

背景:痘病毒由一组大型双链 DNA 病毒组成,已知可导致人类、家畜和其他动物物种患病。痘疹病毒(MPXV;前身为猴痘病毒)、水痘病毒(VARV)和田鼠痘病毒(VPXV)是正痘病毒科属中流行的痘病毒。由痘痘病毒引起的痘痘传染病大流行对全球公共卫生产生了重大影响。迄今为止,只有有限的再利用抗病毒药物和疫苗可用于有效治疗 Mpox 和其他引起传染病的痘病毒:本研究的主要目标是利用免疫信息学和分子建模综合方法,针对三种进化封闭的痘病毒(即 MPXV、VARV 和 VPXV)配制多表位疫苗。DNA依赖性RNA聚合酶(DdRp)是痘病毒的一个潜在疫苗靶点,我们利用它确定了免疫优势B细胞和T细胞表位,然后在原子水平上分析了它与Toll样受体2的相互作用:结果:设计了三种多表位疫苗构建体,即 DdRp_MPXV (V1)、DdRp_VARV (V2) 和 DdRp_VPXV (V3)。这些疫苗构建体具有抗原性、非过敏性、无毒性和可溶性等理想的理化特性。蛋白质-蛋白质对接和相互作用剖析分析表明,目标免疫受体 TLR2 与所设计的疫苗构建体的结构模型之间有很强的结合模式,并表现出许多生化键(氢键、盐桥和非键接触)。最先进的全原子分子动力学模拟显示,在 300 纳秒的整个模拟过程中,疫苗构建体与 TLR2 在原子水平上的相互作用高度稳定。此外,免疫模拟分析结果表明,设计的疫苗有可能诱导针对痘病毒的保护性免疫:综上所述,通过广泛的免疫信息学和分子建模评估,我们发现配制的下一代多价疫苗对密切相关的痘病毒(MPXV、VARV 和 VPXV)具有良好的疗效,但仍需进一步的实验研究。
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Formulation of next-generation polyvalent vaccine candidates against three important poxviruses by targeting DNA-dependent RNA polymerase using an integrated immunoinformatics and molecular modeling approach

Background

Poxviruses comprise a group of large double-stranded DNA viruses and are known to cause diseases in humans, livestock animals, and other animal species. The Mpox virus (MPXV; formerly Monkeypox), variola virus (VARV), and volepox virus (VPXV) are among the prevalent poxviruses of the Orthopoxviridae genera. The ongoing Mpox infectious disease pandemic caused by the Mpox virus has had a major impact on public health across the globe. To date, only limited repurposed antivirals and vaccines are available for the effective treatment of Mpox and other poxviruses that cause contagious diseases.

Methods

The present study was conducted with the primary goal of formulating multi-epitope vaccines against three evolutionary closed poxviruses i.e., MPXV, VARV, and VPXV using an integrated immunoinformatics and molecular modeling approach. DNA-dependent RNA polymerase (DdRp), a potential vaccine target of poxviruses, has been used to determine immunodominant B and T-cell epitopes followed by interactions analysis with Toll-like receptor 2 at the atomic level.

Results

Three multi-epitope vaccine constructs, namely DdRp_MPXV (V1), DdRp_VARV (V2), and DdRp_VPXV (V3) were designed. These vaccine constructs were found to be antigenic, non-allergenic, non-toxic, and soluble with desired physicochemical properties. Protein-protein docking and interaction profiling analysis depicts a strong binding pattern between the targeted immune receptor TLR2 and the structural models of the designed vaccine constructs, and manifested a number of biochemical bonds (hydrogen bonds, salt bridges, and non-bonded contacts). State-of-the-art all-atoms molecular dynamics simulations revealed highly stable interactions of vaccine constructs with TLR2 at the atomic level throughout the simulations on 300 nanoseconds. Additionally, the outcome of the immune simulation analysis suggested that designed vaccines have the potential to induce protective immunity against targeted poxviruses.

Conclusions

Taken together, formulated next-generation polyvalent vaccines were found to have good efficacy against closely related poxviruses (MPXV, VARV, and VPXV) as demonstrated by our extensive immunoinformatics and molecular modeling evaluations; however, further experimental investigations are still needed.

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来源期刊
Journal of Infection and Public Health
Journal of Infection and Public Health PUBLIC, ENVIRONMENTAL & OCCUPATIONAL HEALTH -INFECTIOUS DISEASES
CiteScore
13.10
自引率
1.50%
发文量
203
审稿时长
96 days
期刊介绍: The Journal of Infection and Public Health, first official journal of the Saudi Arabian Ministry of National Guard Health Affairs, King Saud Bin Abdulaziz University for Health Sciences and the Saudi Association for Public Health, aims to be the foremost scientific, peer-reviewed journal encompassing infection prevention and control, microbiology, infectious diseases, public health and the application of healthcare epidemiology to the evaluation of health outcomes. The point of view of the journal is that infection and public health are closely intertwined and that advances in one area will have positive consequences on the other. The journal will be useful to all health professionals who are partners in the management of patients with communicable diseases, keeping them up to date. The journal is proud to have an international and diverse editorial board that will assist and facilitate the publication of articles that reflect a global view on infection control and public health, as well as emphasizing our focus on supporting the needs of public health practitioners. It is our aim to improve healthcare by reducing risk of infection and related adverse outcomes by critical review, selection, and dissemination of new and relevant information in the field of infection control, public health and infectious diseases in all healthcare settings and the community.
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