The Drug-Induced Interface That Drives HIV-1 Integrase Hypermultimerization and Loss of Function
| Author(s) | Singer, Matthew R. | |
| Author(s) | Dinh, Tung | |
| Author(s) | Levintov, Lev | |
| Author(s) | Annamalai, Arun S. | |
| Author(s) | Rey, Juan S. | |
| Author(s) | Briganti, Lorenzo | |
| Author(s) | Cook, Nicola J. | |
| Author(s) | Pye, Valerie E. | |
| Author(s) | Taylor, Ian A. | |
| Author(s) | Kim, Kyungjin | |
| Author(s) | Engelman, Alan N. | |
| Author(s) | Kim, Baek | |
| Author(s) | Perilla, Juan R. | |
| Author(s) | Kvaratskhelia, Mamuka | |
| Author(s) | Cherepanov, Peter | |
| Date Accessioned | 2024-02-28T19:12:39Z | |
| Date Available | 2024-02-28T19:12:39Z | |
| Publication Date | 2023-02-06 | |
| Description | This article was originally published in mBio. The version of record is available at: https://doi.org/10.1128/mbio.03560-22. © 2023 Singer et al. | |
| Abstract | Allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are an emerging class of small molecules that disrupt viral maturation by inducing the aberrant multimerization of IN. Here, we present cocrystal structures of HIV-1 IN with two potent ALLINIs, namely, BI-D and the drug candidate Pirmitegravir. The structures reveal atomistic details of the ALLINI-induced interface between the HIV-1 IN catalytic core and carboxyl-terminal domains (CCD and CTD). Projecting from their principal binding pocket on the IN CCD dimer, the compounds act as molecular glue by engaging a triad of invariant HIV-1 IN CTD residues, namely, Tyr226, Trp235, and Lys266, to nucleate the CTD-CCD interaction. The drug-induced interface involves the CTD SH3-like fold and extends to the beginning of the IN carboxyl-terminal tail region. We show that mutations of HIV-1 IN CTD residues that participate in the interface with the CCD greatly reduce the IN-aggregation properties of Pirmitegravir. Our results explain the mechanism of the ALLINI-induced condensation of HIV-1 IN and provide a reliable template for the rational development of this series of antiretrovirals through the optimization of their key contacts with the viral target. IMPORTANCE Despite the remarkable success of combination antiretroviral therapy, HIV-1 remains among the major causes of human suffering and loss of life in poor and developing nations. To prevail in this drawn-out battle with the pandemic, it is essential to continue developing advanced antiviral agents to fight drug resistant HIV-1 variants. Allosteric integrase inhibitors (ALLINIs) are an emerging class of HIV-1 antagonists that are orthogonal to the current antiretroviral drugs. These small molecules act as highly specific molecular glue, which triggers the aggregation of HIV-1 integrase. In this work, we present high-resolution crystal structures that reveal the crucial interactions made by two potent ALLINIs, namely, BI-D and Pirmitegravir, with HIV-1 integrase. Our results explain the mechanism of drug action and will inform the development of this promising class of small molecules for future use in antiretroviral regimens. | |
| Sponsor | We thank P. Walker and A. Purkiss for the computer support and the help with X-ray data collection arrangements as well as the staff of Diamond Light Source beamline I04 for the assistance during data collection. Synchrotron access was provided via block allocation group MX13775. This work was funded by the US National Institutes of Health grants P50AI150481 (P.C. and A.N.E.) and U54AI170791 (P.C., J.R.P., and A.N.E.), R01AI143649 and U54AI150472 (M.K.), R01AI141327 (B.K.), R37AI039394 (A.N.E.), and P20GM104316 (J.R.P.). The laboratories of P.C. and I.A.T. are supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (CC2058 and CC2029), the UK Medical Research Council (CC2058 and CC2029), and the Wellcome Trust (CC2058 and CC2029). We acknowledge computational support through the Delaware Advanced Research Workforce and Innovation Network (DARWIN) as well as the Caviness cluster. Kyungjin Kim is the chief executive officer of ST Pharm Co. Ltd. No other authors declare a potential conflict of interest. | |
| Citation | Singer MR, Dinh T, Levintov L, Annamalai AS, Rey JS, Briganti L, Cook NJ, Pye VE, Taylor IA, Kim K, Engelman AN,Kim B,Perilla JR, Kvaratskhelia M, Cherepanov P,2023.The Drug-Induced Interface That Drives HIV-1 Integrase Hypermultimerization and Loss of Function. mBio14:e03560-22.https://doi.org/10.1128/mbio.03560-22 | |
| ISSN | 2150-7511 | |
| URL | https://udspace.udel.edu/handle/19716/34071 | |
| Language | en_US | |
| Publisher | mBio | |
| dc.rights | Attribution 4.0 International | en |
| dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
| Keywords | antiretroviral drugs | |
| Keywords | HIV-1 | |
| Keywords | integrase | |
| Keywords | allosteric inhibitor | |
| Keywords | ALLINI | |
| Keywords | LEDGIN | |
| Keywords | Pirmitegravir | |
| Keywords | STP0404 | |
| Keywords | BI-D | |
| Keywords | good health and well-being | |
| Title | The Drug-Induced Interface That Drives HIV-1 Integrase Hypermultimerization and Loss of Function | |
| Type | Article |
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