The coronavirus nsp15 endoribonuclease: A puzzling protein and pertinent antiviral drug target

IF 4.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Antiviral research Pub Date : 2024-05-31 DOI:10.1016/j.antiviral.2024.105921
Benjamin Van Loy, Annelies Stevaert, Lieve Naesens
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Abstract

The SARS-CoV-2 pandemic has bolstered unprecedented research efforts to better understand the pathogenesis of coronavirus (CoV) infections and develop effective therapeutics. We here focus on non-structural protein nsp15, a hexameric component of the viral replication-transcription complex (RTC). Nsp15 possesses uridine-specific endoribonuclease (EndoU) activity for which some specific cleavage sites were recently identified in viral RNA. By preventing accumulation of viral dsRNA, EndoU helps the virus to evade RNA sensors of the innate immune response. The immune-evading property of nsp15 was firmly established in several CoV animal models and makes it a pertinent target for antiviral therapy. The search for nsp15 inhibitors typically proceeds via compound screenings and is aided by the rapidly evolving insight in the protein structure of nsp15. In this overview, we broadly cover this fascinating protein, starting with its structure, biochemical properties and functions in CoV immune evasion. Next, we summarize the reported studies in which compound screening or a more rational method was used to identify suitable leads for nsp15 inhibitor development. In this way, we hope to raise awareness on the relevance and druggability of this unique CoV protein.

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冠状病毒 nsp15 内切核酸酶:令人费解的蛋白质和相关的抗病毒药物靶点。
SARS-CoV-2大流行促进了前所未有的研究工作,以更好地了解冠状病毒(CoV)感染的发病机制并开发有效的治疗方法。我们在此重点研究非结构蛋白 nsp15,它是病毒复制-转录复合体(RTC)的一个六聚体成分。Nsp15 具有尿苷特异性内切核酸酶(EndoU)活性,最近在病毒 RNA 中发现了一些特定的裂解位点。通过阻止病毒 dsRNA 的积累,EndoU 可以帮助病毒躲避先天性免疫反应的 RNA 传感器。nsp15 的免疫排斥特性已在多个 CoV 动物模型中牢固确立,并使其成为抗病毒治疗的相关靶点。寻找 nsp15 抑制剂的工作通常是通过化合物筛选进行的,而对 nsp15 蛋白结构的深入研究也在迅速发展。在本综述中,我们将从 nsp15 的结构、生化特性以及在 CoV 免疫逃避中的功能入手,广泛介绍这一迷人的蛋白质。接下来,我们将总结已报道的研究,在这些研究中,我们采用了化合物筛选或更合理的方法来确定合适的 nsp15 抑制剂开发线索。我们希望通过这种方式提高人们对这种独特的 CoV 蛋白的相关性和可药用性的认识。
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来源期刊
Antiviral research
Antiviral research 医学-病毒学
CiteScore
17.10
自引率
3.90%
发文量
157
审稿时长
34 days
期刊介绍: Antiviral Research is a journal that focuses on various aspects of controlling viral infections in both humans and animals. It is a platform for publishing research reports, short communications, review articles, and commentaries. The journal covers a wide range of topics including antiviral drugs, antibodies, and host-response modifiers. These topics encompass their synthesis, in vitro and in vivo testing, as well as mechanisms of action. Additionally, the journal also publishes studies on the development of new or improved vaccines against viral infections in humans. It delves into assessing the safety of drugs and vaccines, tracking the evolution of drug or vaccine-resistant viruses, and developing effective countermeasures. Another area of interest includes the identification and validation of new drug targets. The journal further explores laboratory animal models of viral diseases, investigates the pathogenesis of viral diseases, and examines the mechanisms by which viruses avoid host immune responses.
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