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Cited by 48HIV/AIDS drug development and treatmentHIV Research and TreatmentComputational Drug Discovery Methods

Discovery of a novel 5-carbonyl-1H-imidazole-4-carboxamide class of inhibitors of the HIV-1 integrase–LEDGF/p75 interaction

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Serrao, Erik, Xu, Zhong-Liang, Debnath, Bikash, Christ, Frauke, Debyser, Zeger, Long, Ya-Qiu, Neamati, Nouri·2013·Bioorganic & Medicinal Chemistry
DOI 10.1016/j.bmc.2013.07.047
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Abstract

Though much progress has been made in the inhibition of HIV-1 integrase catalysis, clinical resistance mutations have limited the promise of long-term drug prescription. Consequently, allosteric inhibition of integrase activity has emerged as a promising approach to antiretroviral discovery and development. Specifically, inhibitors of the interaction between HIV-1 integrase and cellular cofactor LEDGF/p75 have been validated to diminish proviral integration in cells and deliver a potent reduction in viral replicative capacity. Here, we have contributed to the development of novel allosteric integrase inhibitors with a high-throughput AlphaScreen-based random screening approach, with which we have identified novel 5-carbonyl-1H-imidazole-4-carboxamides capable of inhibiting the HIV-1 integrase-LEDGF/p75 interaction in vitro. Following a structure-activity relationship analysis of the initial 1H-imidazole-4,5-dicarbonyl core, we optimized the compound's structure through an industrial database search, and we went further to synthesize a selective and non-cytotoxic panel of inhibitors with enhanced potency.

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Authors
Serrao, E., Xu, Z.-L., Debnath, B., Christ, F., Debyser, Z., Long, Y.-Q., & Neamati, N.
Affiliations
  • University of Southern California (US)
  • Chinese Academy of Sciences (CN)
  • KU Leuven (BE)
Corresponding author
  • Long, Ya-Qiu
  • Neamati, Nouri
ORCID
Venue
Bioorganic & Medicinal Chemistry
Publisher
Elsevier BV
Published
2013-10
Volume
21
Issue
19
Pages
5963-5972
ISSN
0968-0896 (ISSN-L)
DOI
10.1016/j.bmc.2013.07.047
OpenAlex
W1972135201
Cited by
47
References
42
Citations by year
2026: 1 · 2025: 1 · 2024: 3 · 2023: 7 · 2022: 6 · 2021: 6 · 2020: 4 · 2019: 6 · 2018: 3 · 2017: 2 · 2016: 1 · 2015: 3 · 2014: 4
FWCI
1.95
Type
journal article
Language
en
Open access
Licence
Locations
  • Bioorganic & Medicinal Chemistry (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Lirias (submittedVersion)
Funders
  • NIH/NIAID (R21 AI081610)
  • Campbell foundation (N.N.) (81072527, 81021062)
  • National Natural Science Foundation of China
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 integrase, LEDGF/p75, antiretroviral drug discovery, structure-activity relationship, structure-based drug design, integrase resistance mutations
MeSH terms
Aminoimidazole Carboxamide, Binding Sites, Cells, Cultured, Enzyme Activation, Humans, Models, Molecular, Protein Binding, Structure-Activity Relationship, Molecular Structure, HIV Integrase Inhibitors, Inhibitory Concentration 50, Intercellular Signaling Peptides and Proteins, Drug Discovery

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