Evidence map›Paper›PMID 42330848›Full record

ArticleBioorganic chemistry2026

1,4-Dihydroxy-1,8-napthyridinone (DHN) analogs as HIV-1 reverse transcriptase-associated RNase H inhibitors.

Muhammad Syafiq Bin Shahari, Samuel Offei, Huanchun Zhang, Janani Prahlad, Jacob P Mahoney, Karen A Kirby, Stefan G Sarafianos, Zhengqiang Wang

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Article in Bioorganic chemistry, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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4 · The record

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5 · Who and what money

Authors and funding

8 authors.

Muhammad Syafiq Bin ShahariCenter for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, United States.
Samuel OffeiCenter for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, United States.
Huanchun ZhangCenter for ViroScience and Cure, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, GA 30322, United States.
Janani PrahladCenter for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, United States.
Jacob P MahoneyCenter for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, United States.
Karen A KirbyCenter for ViroScience and Cure, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, GA 30322, United States.
Stefan G SarafianosCenter for ViroScience and Cure, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, GA 30322, United States.
Zhengqiang WangCenter for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, United States. Electronic address: wangx472@umn.edu.

Funding

Novel antivirals targeting the RNase H activity of HIV reverse transcriptaseR01AI100890 · NIAID · UNIVERSITY OF MISSOURI-COLUMBIA · PI SARAFIANOS, STEFAN G, WANG, ZHENGQIANG · 2012 to 2016
$3.6M
NIAID NIH HHS R01 AI100890
6 · The paper itself

Abstract

Reverse transcriptase (RT)-associated RNase H (RNH) remains the only virally encoded enzymatic function of HIV-1 yet to be targeted by any drugs approved or in the development pipeline. We have previously developed 1,4-dihydroxy-1,8-napthyridinone (DHN) analogs as potent inhibitors of orthopoxvirus resolvases which belong to the RNase H-like (RNHL) nuclease family featuring a two-metal-dependent catalytic mechanism. In this work, we have enriched the in-house DHN collection to 82 analogs and tested them in HIV-1 in vitro and antiviral assays. In biochemical assays against RT, most analogs inhibited RT RNH activity with low nM to sub-μM potencies without appreciable inhibition against RT polymerase (pol) activity. Structure-activity relationship (SAR) analysis reveals that analogs bearing a phenyl at C-3 with various substitutions at C-5 position are particularly potent. Removing the N-1 hydroxyl group largely abrogated the RNH inhibition, consistent with a two-metal-chelating pharmacophore. In a cell-based antiviral assay against HIV-1 virus, many analogs exhibited sub-μM antiviral activity without significant cytotoxicity. Finally, most analogs were tested against HIV-1 integrase strand transfer (INST) activity which also belongs to the RNHL family. Although some inhibited INST with IC

Indexed as

Anti-HIV AgentsHIV-1HIV Reverse TranscriptaseNaphthyridinesReverse Transcriptase InhibitorsRibonuclease HRibonuclease H, Human Immunodeficiency VirusDose-Response Relationship, DrugHumansMicrobial Sensitivity TestsMolecular StructureStructure-Activity RelationshipAnti-HIV AgentsHIV Reverse TranscriptaseNaphthyridinesreverse transcriptase, Human immunodeficiency virus 1Reverse Transcriptase InhibitorsRibonuclease HRibonuclease H, Human Immunodeficiency VirusAntiviralHIVIntegraseReverse transcriptaseRNase H

Identifiers

PMID42330848
PMCPMC13452264

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