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GRL-142 binds to and impairs HIV-1 integrase nuclear localization signal and potently suppresses highly INSTI-resistant HIV-1 variants.
- Source :
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Science advances [Sci Adv] 2023 Jul 14; Vol. 9 (28), pp. eadg2955. Date of Electronic Publication: 2023 Jul 12. - Publication Year :
- 2023
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Abstract
- Nuclear localization signal (NLS) of HIV-1 integrase (IN) is implicated in nuclear import of HIV-1 preintegration complex (PIC). Here, we established a multiclass drug-resistant HIV-1 variant (HIV <subscript>KGD</subscript> ) by consecutively exposing an HIV-1 variant to various antiretroviral agents including IN strand transfer inhibitors (INSTIs). HIV <subscript>KGD</subscript> was extremely susceptible to a previously reported HIV-1 protease inhibitor, GRL-142, with IC <subscript>50</subscript> of 130 femtomolar. When cells were exposed to HIV <subscript>KGD</subscript> IN-containing recombinant HIV in the presence of GRL-142, significant decrease of unintegrated 2-LTR circular cDNA was observed, suggesting that nuclear import of PIC was severely compromised by GRL-142. X-ray crystallographic analyses revealed that GRL-142 interacts with NLS's putative sequence (DQAEHLK) and sterically blocks the nuclear transport of GRL-142-bound HIV <subscript>KGD</subscript> 's PIC. Highly INSTI-resistant HIV-1 variants isolated from heavily INSTI-experienced patients proved to be susceptible to GRL-142, suggesting that NLS-targeting agents would serve as salvage therapy agents for highly INSTI-resistant variant-harboring individuals. The data should offer a new modality to block HIV-1 infectivity and replication and shed light on developing NLS inhibitors for AIDS therapy.
Details
- Language :
- English
- ISSN :
- 2375-2548
- Volume :
- 9
- Issue :
- 28
- Database :
- MEDLINE
- Journal :
- Science advances
- Publication Type :
- Academic Journal
- Accession number :
- 37436982
- Full Text :
- https://doi.org/10.1126/sciadv.adg2955