Synthesis, Activity, and Structural Analysis of Novel α-Hydroxytropolone Inhibitors of Human Immunodeficiency Virus Reverse Transcriptase-Associated Ribonuclease H
Open accessAbstract
The α-hydroxytroplone, manicol (5,7-dihydroxy-2-isopropenyl-9-methyl-1,2,3,4-tetrahydro-benzocyclohepten-6-one), potently and specifically inhibits ribonuclease H (RNase H) activity of human immunodeficiency virus reverse transcriptase (HIV RT) in vitro. However, manicol was ineffective in reducing virus replication in culture. Ongoing efforts to improve the potency and specificity over the lead compound led us to synthesize 14 manicol derivatives that retain the divalent metal-chelating α-hydroxytropolone pharmacophore. These efforts were augmented by a high resolution structure of p66/p51 HIV-1 RT containing the nonnucleoside reverse transcriptase inhibitor (NNRTI), TMC278 and manicol in the DNA polymerase and RNase H active sites, respectively. We demonstrate here that several modified α-hydroxytropolones exhibit antiviral activity at noncytotoxic concentrations. Inclusion of RNase H active site mutants indicated that manicol analogues can occupy an additional site in or around the DNA polymerase catalytic center. Collectively, our studies will promote future structure-based design of improved α-hydroxytropolones to complement the NRTI and NNRTI currently in clinical use.
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Pyrrolyl diketo acids have good potency against integrase and moderate ribonuclease H inhibition, with antiviral EC50 around micromolar, supporting dual integrase-ribonuclease H inhibitor development.
“Among these derivatives, pyrrolyl diketo acids have shown good potency against IN and moderate inhibition of the RNH, with antiviral EC50 ~μM, demonstrating that identification of dual IN-RNH inhibitors is an attractive strategy for new drug development [83].”
From Retroviral RNase H: structure, mechanism, and inhibition (2021) · cites this paper as [83]
The Introduction (page unavailable) lists diketo acids as a class of RNase H inhibitors. But the paper does not identify pyrrolyl diketo acids or report their integrase potency or antiviral EC50; the micromolar antiviral EC50 values in the Results are for manicol analogs. The Discussion favors developing RNase H inhibitors, not specifically dual integrase–RNase H inhibitors. (LLM, conf=0.83)
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- Authors
- Chung, S., Himmel, D. M., Jiang, J.-K., Wojtak, K., Bauman, J. D., Rausch, J. W., Wilson, J. A., Beutler, J. A., Thomas, C. J., Arnold, E., & Le Grice, S. F. J.
- Affiliations
- Frederick National Laboratory for Cancer Research (US)
- Rutgers, The State University of New Jersey (US)
- National Institutes of Health (US)
- National Cancer Institute (US)
- RT Biochemistry Section, HIV Drug Resistance Program, National Cancer Institute—Frederick, Frederick, Maryland 21702, United States
- ORCID
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2011-06-02
- Volume
- 54
- Issue
- 13
- Pages
- 4462-4473
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- PMC
- PMC3133734
- OpenAlex
- W1996772034
- Cited by
- 80
- References
- 52
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 3 · 2023: 3 · 2022: 5 · 2021: 3 · 2020: 1 · 2019: 5 · 2018: 7 · 2017: 4 · 2016: 10 · 2015: 4 · 2014: 12 · 2013: 10 · 2012: 7
- FWCI
- 6.72
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Rutgers University Community Repository (Rutgers University) (submittedVersion)
- Funders
- National Institutes of Health (Z99 CA999999)
- National Institute of Allergy and Infectious Diseases (AI-27690, R37AI027690, R01AI027690)
- 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-1 reverse transcriptase, non-nucleoside reverse transcriptase inhibitors, antiviral activity, structure-based drug design
- MeSH terms
- Rilpivirine, Benzocycloheptenes, Cations, Divalent, Cell Line, DNA-Directed DNA Polymerase, Humans, Manganese, Models, Molecular, Mutation, Nitriles, Protein Conformation, Pyrimidines, Structure-Activity Relationship, Tropolone, Virus Replication, Molecular Structure, HIV-1, Crystallography, X-Ray, Anti-HIV Agents, Catalytic Domain, HIV Reverse Transcriptase, Ribonuclease H, Human Immunodeficiency Virus, Coordination Complexes
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