Format

Send to

Choose Destination
Elife. 2017 Oct 17;6. pii: e28020. doi: 10.7554/eLife.28020.

A novel central nervous system-penetrating protease inhibitor overcomes human immunodeficiency virus 1 resistance with unprecedented aM to pM potency.

Author information

1
Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, United States.
2
Department of Hematology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.
3
Department of Rheumatology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.
4
Department of Infectious Diseases, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.
5
Department of Medical Technology, Kumamoto Health Science University, Kumamoto, Japan.
6
National Center for Global Health and Medicine Research Institute, Tokyo, Japan.
7
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, United States.
8
Department of Chemistry, Purdue University, West Lafayette, United States.
9
Retroviral Disease Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, United States.
10
Bioanalysis Group, Drug Metabolism and Analysis Department, Nonclinical Research Center, Drug Development Service Segment, LSI Medience Corporation, Tokyo, Japan.
11
Protein Crystal Analysis Division, Japan Synchrotron Radiation Research Institute, Hyogo, Japan.
12
Innovative Collaboration Organization, Kumamoto University, Kumamoto, Japan.
13
Department of Pharmacy, Kumamoto University Hospital, Kumamoto, Japan.
14
Department of Environmental and Molecular Health Sciences, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.

Abstract

Antiretroviral therapy for HIV-1 infection/AIDS has significantly extended the life expectancy of HIV-1-infected individuals and reduced HIV-1 transmission at very high rates. However, certain individuals who initially achieve viral suppression to undetectable levels may eventually suffer treatment failure mainly due to adverse effects and the emergence of drug-resistant HIV-1 variants. Here, we report GRL-142, a novel HIV-1 protease inhibitor containing an unprecedented 6-5-5-ring-fused crown-like tetrahydropyranofuran, which has extremely potent activity against all HIV-1 strains examined with IC50 values of attomolar-to-picomolar concentrations, virtually no effects on cellular growth, extremely high genetic barrier against the emergence of drug-resistant variants, and favorable intracellular and central nervous system penetration. GRL-142 forms optimum polar, van der Waals, and halogen bond interactions with HIV-1 protease and strongly blocks protease dimerization, demonstrating that combined multiple optimizing elements significantly enhance molecular and atomic interactions with a target protein and generate unprecedentedly potent and practically favorable agents.

KEYWORDS:

CNS penetration; GRL-142; drug-resistant HIV-1; infectious disease; microbiology; protease inhibitor; virus

PMID:
29039736
PMCID:
PMC5644950
DOI:
10.7554/eLife.28020
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for eLife Sciences Publications, Ltd Icon for PubMed Central
Loading ...
Support Center