Enhancing the solubility of SARS-CoV-2 inhibitors to increase future prospects for clinical development.

IF 4 2区 医学 Q2 VIROLOGY
Journal of Virology Pub Date : 2025-03-18 Epub Date: 2025-02-04 DOI:10.1128/jvi.02159-24
Ariel J Kuhn, Victor K Outlaw, Tara C Marcink, Zhen Yu, Megan C Mears, Maria N Cajimat, Dale F Kreitler, Payton R Cleven, Jee Ching Mook, Dennis A Bente, Matteo Porotto, Samuel H Gellman, Anne Moscona
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引用次数: 0

Abstract

SARS-CoV-2 poses an ongoing threat to human health as variants continue to emerge. Several effective vaccines are available, but a diminishing number of Americans receive the updated vaccines (only 22% received the 2023 update). Public hesitancy towards vaccines and common occurrence of "breakthrough" infections (i.e., infections of vaccinated individuals) highlight the need for alternative methods to reduce viral transmission. SARS-CoV-2 enters cells by fusing its envelope with the target cell membrane in a process mediated by the viral spike protein, S. The S protein operates via a Class I fusion mechanism in which fusion between the viral envelope and host cell membrane is mediated by structural rearrangements of the S trimer. We previously reported lipopeptides derived from the C-terminal heptad repeat (HRC) domain of SARS-CoV-2 S that potently inhibit fusion by SARS-CoV-2, both in vitro and in vivo. These lipopeptides bear an attached cholesterol unit to anchor them in the membrane. Here, to improve prospects for experimental development and future clinical utility, we employed structure-guided design to incorporate charged residues at specific sites in the peptide to enhance aqueous solubility. This effort resulted in two new, potent lipopeptide inhibitors.

Importance: Despite the existence of vaccines for SARS-CoV-2, the constant evolution of new variants and the occurrence of breakthrough infections highlight the need for new and effective antiviral approaches. We have shown that lipopeptides designed to bind a conserved region on the SARS-CoV-2 spike protein can effectively block viral entry into cells and thereby block infection. To support the feasibility of using this approach in humans, we re-designed these lipopeptides to be more soluble, using information about the structure of the spike protein interacting with the peptides to modify the peptide chain. The new peptides are effective against both SARS-CoV-2 and MERS. The lipopeptides described here could serve as treatment for people who are unvaccinated or who experience breakthrough infections, and the approach to increasing solubility can be applied in a broad spectrum approach to treating infections with emerging viruses.

增强SARS-CoV-2抑制剂的溶解度,以增加未来临床开发的前景。
随着变体的不断出现,SARS-CoV-2对人类健康构成持续威胁。有几种有效的疫苗可用,但接种更新疫苗的美国人越来越少(只有22%的人接种了2023年的更新疫苗)。公众对疫苗的犹豫和“突破性”感染(即接种疫苗的个人感染)的普遍发生突出表明需要其他方法来减少病毒传播。SARS-CoV-2通过病毒刺突蛋白S介导的包膜与靶细胞膜融合进入细胞,S蛋白通过I类融合机制运作,其中病毒包膜与宿主细胞膜的融合是通过S三聚体的结构重排介导的。我们之前报道了从SARS-CoV-2 S的c端七肽重复(HRC)结构域衍生的脂肽,在体外和体内均能有效抑制SARS-CoV-2的融合。这些脂肽带有一个附加的胆固醇单位,将它们固定在膜上。在这里,为了改善实验发展前景和未来的临床应用,我们采用结构引导设计在肽的特定位点加入带电残基以提高水溶性。这一努力产生了两种新的、有效的脂肽抑制剂。重要性:尽管存在针对SARS-CoV-2的疫苗,但新变种的不断演变和突破性感染的发生突出表明需要新的有效抗病毒方法。我们已经证明,设计用于结合SARS-CoV-2刺突蛋白上的保守区域的脂肽可以有效地阻止病毒进入细胞,从而阻止感染。为了支持在人类中使用这种方法的可行性,我们重新设计了这些脂肽,使其更易于溶解,利用与肽相互作用的刺突蛋白结构信息来修饰肽链。新多肽对SARS-CoV-2和MERS都有效。这里描述的脂肽可以作为未接种疫苗或经历突破性感染的人的治疗方法,并且增加溶解度的方法可以应用于治疗新发病毒感染的广谱方法。
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
Journal of Virology
Journal of Virology 医学-病毒学
CiteScore
10.10
自引率
7.40%
发文量
906
审稿时长
1 months
期刊介绍: Journal of Virology (JVI) explores the nature of the viruses of animals, archaea, bacteria, fungi, plants, and protozoa. We welcome papers on virion structure and assembly, viral genome replication and regulation of gene expression, genetic diversity and evolution, virus-cell interactions, cellular responses to infection, transformation and oncogenesis, gene delivery, viral pathogenesis and immunity, and vaccines and antiviral agents.
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