An Allosteric Mechanism for Inhibiting HIV-1 Integrase with a Small Molecule
Open accessAbstract
HIV-1 integrase (IN) is a validated target for developing antiretroviral inhibitors. Using affinity acetylation and mass spectrometric (MS) analysis, we previously identified a tetra-acetylated inhibitor (2E)-3-[3,4-bis(acetoxy)phenyl]-2-propenoate-N-[(2E)-3-[3,4-bis(acetyloxy)phenyl]-1-oxo-2-propenyl]-L-serine methyl ester; compound 1] that selectively modified Lys173 at the IN dimer interface. Here we extend our efforts to dissect the mechanism of inhibition and structural features that are important for the selective binding of compound 1. Using a subunit exchange assay, we found that the inhibitor strongly modulates dynamic interactions between IN subunits. Restricting such interactions does not directly interfere with IN binding to DNA substrates or cellular cofactor lens epithelium-derived growth factor, but it compromises the formation of the fully functional nucleoprotein complex. Studies comparing compound 1 with a structurally related IN inhibitor, the tetra-acetylated-chicoric acid derivative (2R,3R)-2,3-bis[[(2E)-3-[3,4-bis(acetyloxy)phenyl]-1-oxo-2-propen-1-yl]oxy]-butanedioic acid (compound 2), indicated striking mechanistic differences between these agents. The structures of the two inhibitors differ only in their central linker regions, with compounds 1 and 2 containing a single methyl ester group and two carboxylic acids, respectively. MS experiments highlighted the importance of these structural differences for selective binding of compound 1 to the IN dimer interface. Moreover, molecular modeling of compound 1 complexed to IN identified a potential inhibitor binding cavity and provided structural clues regarding a possible role of the central methyl ester group in establishing an extensive hydrogen bonding network with both interacting subunits. The proposed mechanism of action and binding site for the small-molecule inhibitor identified in the present study provide an attractive venue for developing allosteric inhibitors of HIV-1 IN.
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Cites
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BackgroundSelf-citationAllosteric inhibition of HIV-1 integrase activity
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MethodSlaughter, A., Jurado, K. A., Deng, N., Feng, L., Kessl, J. J., Shkriabai, N., Larue, R. C., Fadel, H. J., Patel, P. A., Jena, N., et al. (2014) · Retrovirology · doi:10.1186/s12977-014-0100-1 · Cited by 38 · see citing works
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“For example, a small molecule N,O-bis(3,4,-diacetyloxycinnamoyl)-serinate [referred in (Kessl et al. 2009) and here as compound 1] has been shown to bind at the IN dimer interface and stabilize interacting subunits into an inactive multimeric form Kessl et al.”
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Tintori, C., Demeulemeester, J., Franchi, L., Massa, S., Debyser, Z., Christ, F., & Botta, M. (2012) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2012.03.064 · Cited by 31 · see citing works
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Different Pathways Leading to Integrase Inhibitors Resistance
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“Other peptides were developed to specifically impair IN oligomerization belonging to the “shiftides” family (Kessl et al., 2009; Maes et al., 2012).”
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“As further proof-of-principal we have recently shown that a small molecule inhibitor can stabilize a functionally compromised multimeric form of HIV-1 IN [134].”
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“Therefore, the proposed atomistic-level model of the allosteric inhibition mechanism of LEDGINs to the HIV-1 IN CCD active site shown in Figure 10 can help to understand the experimental results that LEDGINs engage the LEDGF/p75 binding site impair the inherent HIV-1 IN catalytic activity [19,20,22,23].”
BackgroundA Ligand-Based Virtual Screening Method Using Direct Quantification of Generalization Ability
Dai, W., & Guo, D. (2019) · Molecules · doi:10.3390/molecules24132414 · Cited by 12
A Symmetric Region of the HIV-1 Integrase Dimerization Interface Is Essential for Viral Replication
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“Rational drug design efforts have thus far been mainly directed toward developing compounds that bind to the Mg-coordinating active site, but it has become apparent that new classes of allosteric inhibitors that disrupt IN-cofactor interactions [32,33] or IN multimerization [34] will be necessary to advance the antire…”
BackgroundMethods for the Analyses of Inhibitor-Induced Aberrant Multimerization of HIV-1 Integrase
Kessl, J. J., Sharma, A., & Kvaratskhelia, M. (2015) · Methods in molecular biology · doi:10.1007/978-1-4939-3046-3_10 · Cited by 8 · see citing works
“Initial proof-of-concept studies have shown that IN activity can be compromised by small-molecule tetra-acetylated chicoric acid binding at the IN dimer interface and stabilizing interacting IN subunits into incorrectly assembled multimeric states [16, 17].”
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Prospective strategies for targeting HIV-1 integrase function
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“Disruption of the IN dimer has also been demonstrated in vitro by selective binding of a tetra-acetylated peptide inhibitor to the dimer interface and also made possible the mapping of a previously unknown inhibitor binding site on IN [35].”
BackgroundInfluentialBrief Histories of Retroviral Integration Research and Associated International Conferences
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“Dr. Kvaratskhelia suggested that the highly dynamic behavior of IN subunit-subunit interactions could be exploited as a novel antiviral target and presented preliminary studies with an acetylated molecule that engaged IN at the CCD-CCD dimer interface and restricted protein subunit exchange [110].”
BackgroundHIV-1 Integrase Drug Discovery Comes of Age
Demeulemeester, J., Maeyer, M. D., & Debyser, Z. (2013) · Topics in medicinal chemistry · doi:10.1007/7355_2013_33 · Cited by 8 · see citing works
Corona, A., Meleddu, R., Delelis, O., Subra, F., Cottiglia, F., Esposito, F., Distinto, S., Maccioni, E., & Tramontano, E. (2023) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2023.1193280 · Cited by 3
“, 2008) (2E)-3-[3,4-bis(acetoxy)phenyl]-2-propenoate-N[(2E)-3-[3,4-bis(acetyloxy)phenyl]-1-oxo-2-propenyl]-L-serine methyl ester (Kessl et al., 2009).”
Computational Methods in Mass Spectrometry-Based Protein 3D Studies
Vitale, R., Renzone, G., Scaloni, A., & Amodeo, P. (2011) · InTech eBooks · doi:10.5772/19635 · Cited by 1 · see citing works
“…Methods in Mass Spectrometry-Based Protein 3D Studies 143 In general, MS-based data can be used to limit the protein region to be sampled (Kessl et al., 2009) or can be explicitly considered in the docking procedure, as in the case of the mapping of Sso7d ATPase site (Renzone et al.,…”
MethodTocco, G., Laus, A., Casula, M., Caboni, P., Beutler, J. A., Tramontano, E., & Esposito, F. (2025) · Molecules · doi:10.3390/molecules30244709
“This regulation not only encourages and stabilizes the multimerization of IN but also prevents the IN-IN subunit exchange essential for the IN-DNA complex formation [13].”
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“Il a été démontré que les INLAIs sont capables de se lier à l’interface du dimère CCD-CCD IN, sur le site d’interaction avec LEDGF, possèdent une activité supplémentaire conduisant à la formation de multimères d’IN [346,347,348].”
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Prasad, V. R., & Kalpana, G. (2016) · Methods in Molecular Biology · doi:10.1007/978-1-4939-3046-3
“The latter can be inputted into RNA structure viewers such as PseudoViewer [17] or Varna [18] to produce publicationquality images.”
Background
- Authors
- Kessl, J. J., Eidahl, J. O., Shkriabai, N., Zhao, Z., McKee, C. J., Hess, S., Burke, T. R., & Kvaratskhelia, M.
- Affiliations
- The Ohio State University (US)
- California Institute of Technology (US)
- Corresponding author
- Kvaratskhelia, Mamuka
- Venue
- Molecular Pharmacology
- Publisher
- Elsevier BV
- Published
- 2009-10
- Volume
- 76
- Issue
- 4
- Pages
- 824-832
- ISSN
- 0026-895X (ISSN-L)
- PMC
- PMC2769043
- OpenAlex
- W2126391063
- Cited by
- 50
- References
- 0
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 1 · 2021: 1 · 2020: 3 · 2019: 2 · 2018: 1 · 2017: 1 · 2016: 1 · 2015: 4 · 2014: 5 · 2013: 8 · 2012: 9
- FWCI
- 4.83
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Pharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- Funders
- National Institutes of Health (AI062520)
- National Cancer Institute
- National Institute of Allergy and Infectious Diseases (AI062520, R01AI062520, K02AI077341, AI077341)
- National Institute of Diabetes and Digestive and Kidney Diseases
- Topics
- Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Keywords
- HIV-1 integrase, allosteric inhibition, small molecule inhibitors, nucleoprotein complexes, LEDGF, inhibitor binding site, hydrogen bond network, antiretroviral drug design
- MeSH terms
- Amino Acid Sequence, Chromatography, Gel, Models, Molecular, Molecular Sequence Data, Peptides, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, HIV Integrase, HIV Integrase Inhibitors
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