Design, synthesis, and biological evaluations of hydroxypyridonecarboxylic acids as inhibitors of HIV reverse transcriptase associated RNase H
Open accessAbstract
Targeting the clinically unvalidated reverse transcriptase (RT) associated ribonuclease H (RNase H) for human immunodeficiency virus (HIV) drug discovery generally entails chemotypes capable of chelating two divalent metal ions in the RNase H active site. The hydroxypyridonecarboxylic acid scaffold has been implicated in inhibiting homologous HIV integrase (IN) and influenza endonuclease via metal chelation. We report herein the design, synthesis, and biological evaluations of a novel variant of the hydroxypyridonecarboxylic acid scaffold featuring a crucial N-1 benzyl or biarylmethyl moiety. Biochemical studies show that most analogues consistently inhibited HIV RT-associated RNase H in the low micromolar range in the absence of significant inhibition of RT polymerase or IN. One compound showed reasonable cell-based antiviral activity (EC50 = 10 μM). Docking and crystallographic studies corroborate favorable binding to the active site of HIV RNase H, providing a basis for the design of more potent analogues.
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Catalytic activity of rnhA ribonuclease H proteins requires an active-site DEDD motif and a conserved active-site histidine.
“For the catalytic activity of rnhA RNH proteins, site-directed mutagenesis, thermal stability and structural determination studies have indicated that an active-site DEDD motif and conserved active-site histidine are required [43-50]”
From Retroviral RNase H: structure, mechanism, and inhibition (2021) · cites this paper as [43]
The Molecular modeling section identifies D443, E478, D498 and D549 as essential active-site residues for HIV reverse transcriptase–associated RNase H. It says an interaction involving H539 may affect catalytic efficiency, but does not establish that histidine is required. The paper addresses HIV RT-associated RNase H, not rnhA proteins; page numbers are unavailable in our copy. (LLM, conf=0.86)
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- Authors
- Kankanala, J., Kirby, K. A., Liu, F., Miller, L., Nagy, E., Wilson, D. J., Parniak, M. A., Sarafianos, S. G., & Wang, Z.
- Affiliations
- University of Minnesota (US)
- University of Missouri (US)
- University of Pittsburgh (US)
- Corresponding author
- Wang, Zhengqiang
- ORCID
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2016-04-29
- Volume
- 59
- Issue
- 10
- Pages
- 5051-5062
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- PMC
- PMC4882222
- OpenAlex
- W2340892054
- Semantic Scholar
- 38684d4eeff907c907da3f18279f0c3c3876290f
- Cited by
- 66
- References
- 42
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 5 · 2023: 7 · 2022: 3 · 2021: 10 · 2020: 3 · 2019: 11 · 2018: 10 · 2017: 10 · 2016: 1
- FWCI
- 10.16
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (AI100890)
- Center for Drug Design, University of Minnesota
- Topics
- Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Keywords
- HIV reverse transcriptase, RNase H, metal chelation, divalent metal ions, HIV integrase, antiviral agents, structure-activity relationship, crystal structure, molecular docking
- MeSH terms
- Cyclobutanes, Dose-Response Relationship, Drug, Humans, Pyridines, Structure-Activity Relationship, Drug Design, Molecular Structure, Reverse Transcriptase Inhibitors, HIV Reverse Transcriptase, Ribonuclease H, Human Immunodeficiency Virus, Molecular Docking Simulation
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