2. Academic Validation
  3. GRL-142 binds to and impairs HIV-1 integrase nuclear localization signal and potently suppresses highly INSTI-resistant HIV-1 variants

GRL-142 binds to and impairs HIV-1 integrase nuclear localization signal and potently suppresses highly INSTI-resistant HIV-1 variants

  • Sci Adv. 2023 Jul 14;9(28):eadg2955. doi: 10.1126/sciadv.adg2955.
Manabu Aoki 1 2 3,  Hiromi Aoki-Ogata 1 3,  Haydar Bulut 1,  Hironori Hayashi 4 5,  Nobutoki Takamune 6,  Naoki Kishimoto 6,  Hiroki Tanaka 7,  Nobuyo Higashi-Kuwata 3,  Shin-Ichiro Hattori 3,  Debananda Das 1,  Kalapala Venkateswara Rao 8,  Kazuya Iwama 4 5,  David A Davis 9,  Kazuya Hasegawa 10,  Kazutaka Murayama 11,  Robert Yarchoan 9,  Arun K Ghosh 8,  Alice K Pau 12,  Shinichi Machida 7,  Shogo Misumi 6,  Hiroaki Mitsuya 1 3 13
Affiliations

Affiliations

  • 1 Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • 2 Department of Medical Technology, Kumamoto Health Science University, Kumamoto, Japan.
  • 3 Department of Refractory Viral Diseases, National Center for Global Health and Medicine Research Institute, Tokyo, Japan.
  • 4 Department of Intelligent Network for Infection Control, Tohoku University Graduate School of Medicine, Miyagi, Japan.
  • 5 Department of infectious Diseases, International Research Institute of Disaster Science, Tohoku University, Miyagi, Japan.
  • 6 Department of Environmental and Molecular Health Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
  • 7 Department of Structural Virology, National Center for Global Health and Medicine Research Institute, Tokyo, Japan.
  • 8 Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, IN, USA.
  • 9 Viral Oncology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • 10 Structural Biology Division, Japan Synchrotron Radiation Research Institute, Hyogo, Japan.
  • 11 Division of Biomedical Measurements and Diagnostics, Graduate School of Biomedical Engineering, Tohoku University, Miyagi, Japan.
  • 12 National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
  • 13 Division of Clinical Sciences, Kumamoto University Hospital, Kumamoto, Japan.
PMID: 37436982 DOI: 10.1126/sciadv.adg2955
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 (HIVKGD) by consecutively exposing an HIV-1 variant to various antiretroviral agents including IN strand transfer inhibitors (INSTIs). HIVKGD was extremely susceptible to a previously reported HIV-1 Protease inhibitor, GRL-142, with IC50 of 130 femtomolar. When cells were exposed to HIVKGD 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 HIVKGD'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.

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