LAVR-289, an Acyclo-Nucleoside Phosphonate, Has Broad-Spectrum Activity against Herpesviruses.

IF 4 2区医学 Q2 CHEMISTRY, MEDICINAL

ACS Infectious Diseases Pub Date : 2025-05-17 DOI:10.1021/acsinfecdis.5c00171

Sandrine Kappler-Gratias, Charlotte Quentin-Froignant, Elie Marcheteau, José Fernandez, David Boutolleau, Virginie Garcia, Vincent Roy, Luigi A Agrofoglio, Franck Gallardo

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Abstract

Human herpesviruses are large dsDNA viruses that primarily cause opportunistic infections in healthy adults but can trigger life-threatening infections in immunocompromised patients. Previously, antivirals have been developed against a variety of herpesviruses; these include acyclovir for herpes simplex viruses (HSV1 and 2) and ganciclovir and letermovir for human cytomegalovirus (hCMV). However, broad-spectrum inhibitors of herpesvirus infections are still lacking. Here we report the efficacy of LAVR-289, a new acyclic nucleoside analogue, on a broad range of herpesviruses of human and animal origin. LAVR-289 displays nanomolar efficacy in vitro, is active on viral strains resistant to gold-standard antivirals and is efficacious ex vivo on reconstituted human skin infected with HSV1. In addition, the activity of LAVR-289 against poxviruses and adenoviruses is an indication of its potential for the management of opportunistic virus infections in immunocompromised patients.

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LAVR-289是一种无环核苷膦酸盐，对疱疹病毒具有广谱活性。

人类疱疹病毒是大型dsDNA病毒，主要在健康成人中引起机会性感染，但在免疫功能低下的患者中可引发危及生命的感染。此前，针对多种疱疹病毒已开发出抗病毒药物；这些药物包括治疗单纯疱疹病毒（HSV1和2）的阿昔洛韦和治疗人类巨细胞病毒（hCMV）的更昔洛韦和莱特莫韦。然而，疱疹病毒感染的广谱抑制剂仍然缺乏。在这里，我们报告了LAVR-289，一种新的无环核苷类似物，对广泛的人类和动物源疱疹病毒的功效。LAVR-289在体外表现出纳摩尔效应，对金标准抗病毒药物耐药的病毒株有活性，在体外对感染HSV1的重组人皮肤有效。此外，LAVR-289对痘病毒和腺病毒的活性表明其在治疗免疫功能低下患者的机会性病毒感染方面具有潜力。

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来源期刊

ACS Infectious Diseases CHEMISTRY, MEDICINALINFECTIOUS DISEASES&nb-INFECTIOUS DISEASES

CiteScore

9.70

自引率

3.80%

发文量

213

期刊介绍： ACS Infectious Diseases will be the first journal to highlight chemistry and its role in this multidisciplinary and collaborative research area. The journal will cover a diverse array of topics including, but not limited to: * Discovery and development of new antimicrobial agents — identified through target- or phenotypic-based approaches as well as compounds that induce synergy with antimicrobials. * Characterization and validation of drug target or pathways — use of single target and genome-wide knockdown and knockouts, biochemical studies, structural biology, new technologies to facilitate characterization and prioritization of potential drug targets. * Mechanism of drug resistance — fundamental research that advances our understanding of resistance; strategies to prevent resistance. * Mechanisms of action — use of genetic, metabolomic, and activity- and affinity-based protein profiling to elucidate the mechanism of action of clinical and experimental antimicrobial agents. * Host-pathogen interactions — tools for studying host-pathogen interactions, cellular biochemistry of hosts and pathogens, and molecular interactions of pathogens with host microbiota. * Small molecule vaccine adjuvants for infectious disease. * Viral and bacterial biochemistry and molecular biology.