Abstract
We describe here the design, synthesis, and X-ray structural studies of a new class of HIV-1 protease inhibitors containing 8-oxabicyclo[3.2.1]octanol-derived P2 ligands. We investigated the functional effect of these stereochemically defined fused-poly cyclic ligands on enzyme inhibition and antiviral activity in MT-2 cells. The tricyclic core of 8-oxabicyclo[3.2.1]octan-6-ol is designed to interact with the residues in the S2 subsite of HIV-1 protease. The syntheses of the ligands were carried out using the [5+2]-cycloaddition as the key step. Several inhibitors exhibited potent enzyme inhibitory activity. High resolution room-temperature X-ray structures of inhibitor-bound HIV-1 protease were determined. These structures provided important molecular insights for further design and optimization of inhibitor potency.
| Original language | English |
|---|---|
| Article number | 130109 |
| Journal | Bioorganic and Medicinal Chemistry Letters |
| Volume | 120 |
| DOIs | |
| State | Published - May 1 2025 |
Funding
This research was supported by the National Institutes of Health (Grant AI150466, AKG). X-ray data were collected on the in-house X-ray diffractometer at the Neutron Scattering Division, Oak Ridge National Laboratory (ORNL) supported by the Scientific User Facilities Division, Office of Basic Energy Sciences, U.S. Department of Energy. ORNL is managed by UT-Battelle LLC for DOE's Office of Science. This work was also supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health (HM), and in part by grants for the promotion of AIDS research from the Ministry of Health; grants from Welfare and Labor of Japan (HM); grants for the Research Program on HIV/AIDS from the Japan Agency for Medical Research and Development (AMED) under grant numbers JP15fk0410001 and JP16fk041001 (HM); a grant from the National Center for Global Health and Medicine (NCGM) Research Institute (HM); and a Grant-in-Aid for Scientific Research and a Grant-in-Aid for Challenging Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (Monbu Kagakusho)(HM). The authors would like to thank the Purdue University Center for Cancer Research, which supports the shared NMR and mass spectrometry facilities. This research was supported by the National Institutes of Health (Grant AI150466, AKG). X-ray data were collected on the in-house X-ray diffractometer at the Neutron Scattering Division, Oak Ridge National Laboratory (ORNL) supported by the Scientific User Facilities Division, Office of Basic Energy Sciences, U.S. Department of Energy. ORNL is managed by UT-Battelle LLC for DOE’s Office of Science. This work was also supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health (HM), and in part by grants for the promotion of AIDS research from the Ministry of Health; grants from Welfare and Labor of Japan (HM); grants for the Research Program on HIV/AIDS from the Japan Agency for Medical Research and Development (AMED) under grant numbers JP15fk0410001 and JP16fk041001 (HM); a grant from the National Center for Global Health and Medicine (NCGM) Research Institute (HM); and a Grant-in-Aid for Scientific Research and a Grant-in-Aid for Challenging Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (Monbu Kagakusho)(HM). The authors would like to thank the Purdue University Center for Cancer Research, which supports the shared NMR and mass spectrometry facilities.
Keywords
- Cyclic ligands
- Cycloaddition
- HIV-1 protease
- Inhibitor
- X-ray structure