Cutting into the substrate dominance: pharmacophore and structure-based approaches toward inhibiting human immunodeficiency virus reverse transcriptase-associated ribonuclease H
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Conspectus Human immunodeficiency virus (HIV) reverse transcriptase (RT) contains two distinct functional domains: a DNA polymerase (pol) domain and a ribonuclease H (RNase H) domain, both of which are required for viral genome replication. Over the last 3 decades, RT has been at the forefront of HIV drug discovery efforts with numerous nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) approved by the FDA. However, all these RT inhibitors target only the pol function, and inhibitors of RT-associated RNase H have yet to enter the development pipeline, which in itself manifests both the opportunity and challenges of targeting RNase H: if developed, RT RNase H inhibitors would represent a mechanistically novel class of HIV drugs that can be particularly valuable in treating HIV strains resistant to current drugs. The challenges include (1) the difficulty in selectively targeting RT RNase H over RT pol due to their close interplay both spatially and temporally and over HIV-1 integrase strand transfer (INST) activity because of their active site similarities; (2) to a larger extent, the inability of active site inhibitors to confer significant antiviral effect, presumably due to a steep substrate barrier by which the pre-existing substrate prevents access of small molecules to the active site. As a result, previously reported RT RNase H inhibitors typically lacked target specificity and significant antiviral potency. Achieving meaningful antiviral activity via active site targeting likely entails selective and ultrapotent RNase H inhibition to allow small molecules to cut into the dominance of substrates. Based on a pharmacophore model informed by prior work, we designed and redesigned a few metal-chelating chemotypes, such as 2-hydroxyisoquinolinedione (HID), hydroxypyridonecarboxylic acid (HPCA), 3-hydroxypyrimidine-2,4-dione (HPD), and N -hydroxythienopyrimidine-2,4-dione (HTPD). Analogues of these chemotypes generally exhibited improved potency and selectivity inhibiting RT RNase H over the best previous compounds and further validated the pharmacophore model. Extended structure–activity relationship (SAR) on the HPD inhibitor type by mainly altering the linkage generated a few subtypes showing exceptional potency (single-digit nanomolar) and excellent selectivity over the inhibition of RT pol and INST. In parallel, a structure-based approach also allowed us to design a unique double-winged HPD subtype to potently and selectively inhibit RT RNase H and effectively compete against the RNA/DNA substrate. Significantly, all potent HPD subtypes consistently inhibited HIV-1 in the cell culture, suggesting that carefully designed active site RNase H inhibitors with ultrapotency could partially overcome the barrier to antiviral phenotype. Overall, in addition to identifying our own inhibitor types, our medicinal chemistry efforts demonstrated the value of pharmacophore and structure-based approaches in designing active side-directed RNase H inhibitors and could provide a viable path to validating RNase H as a novel antiviral target.
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Significant progress has been made in developing active-site ribonuclease H inhibitors.
“During the past several years, significant progress has been made in the development of active-site RNH inhibitors [32-35].”
From Retroviral RNase H: structure, mechanism, and inhibition (2021) · cites this paper as [35]
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- Authors
- Wang, L., Sarafianos, S. G., & Wang, Z.
- Affiliations
- Dalian University of Technology (CN)
- Emory University (US)
- University of Minnesota (US)
- Corresponding author
- Wang, Zhengqiang
- Venue
- Accounts of Chemical Research
- Publisher
- American Chemical Society (ACS)
- Published
- 2019-12-27
- Volume
- 53
- Issue
- 1
- Pages
- 218-230
- ISSN
- 0001-4842 (ISSN-L)
- 1520-4898
- PMC
- PMC7144833
- OpenAlex
- W2998454564
- Cited by
- 43
- References
- 59
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 5 · 2023: 6 · 2022: 6 · 2021: 10 · 2020: 4
- FWCI
- 0.77
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- Locations
- Accounts of Chemical Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (AI100890)
- University of Minnesota
- Topics
- Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Keywords
- HIV reverse transcriptase, RNase H, RNase H inhibitors, pharmacophore model, structure-based drug design, structure-activity relationship, HIV drug resistance, antiviral potency
- MeSH terms
- Humans, Models, Molecular, Molecular Structure, Reverse Transcriptase Inhibitors, HIV Reverse Transcriptase, Ribonuclease H, Human Immunodeficiency Virus
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