The Novel hDHODH Inhibitor MEDS433 Prevents Influenza Virus Replication by Blocking Pyrimidine Biosynthesis

Author:

Sibille GiuliaORCID,Luganini AnnaORCID,Sainas StefanoORCID,Boschi DonatellaORCID,Lolli Marco Lucio,Gribaudo GiorgioORCID

Abstract

The pharmacological management of influenza virus (IV) infections still poses a series of challenges due to the limited anti-IV drug arsenal. Therefore, the development of new anti-influenza agents effective against antigenically different IVs is therefore an urgent priority. To meet this need, host-targeting antivirals (HTAs) can be evaluated as an alternative or complementary approach to current direct-acting agents (DAAs) for the therapy of IV infections. As a contribution to this antiviral strategy, in this study, we characterized the anti-IV activity of MEDS433, a novel small molecule inhibitor of the human dihydroorotate dehydrogenase (hDHODH), a key cellular enzyme of the de novo pyrimidine biosynthesis pathway. MEDS433 exhibited a potent antiviral activity against IAV and IBV replication, which was reversed by the addition of exogenous uridine and cytidine or the hDHODH product orotate, thus indicating that MEDS433 targets notably hDHODH activity in IV-infected cells. When MEDS433 was used in combination either with dipyridamole (DPY), an inhibitor of the pyrimidine salvage pathway, or with an anti-IV DAA, such as N4-hydroxycytidine (NHC), synergistic anti-IV activities were observed. As a whole, these results indicate MEDS433 as a potential HTA candidate to develop novel anti-IV intervention approaches, either as a single agent or in combination regimens with DAAs.

Funder

Italian Ministry for Universities and Scientific Research

Regione Piemonte

North Atlantic Treaty Organization

Ministero degli Affari Esteri e della Cooperazione Internazionale

Italian Association for Cancer Research

Publisher

MDPI AG

Subject

Virology,Infectious Diseases

Reference58 articles.

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3