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Sci Rep. 2017 Sep 25;7(1):12235. doi: 10.1038/s41598-017-12052-9.

GRL-09510, a Unique P2-Crown-Tetrahydrofuranylurethane -Containing HIV-1 Protease Inhibitor, Maintains Its Favorable Antiviral Activity against Highly-Drug-Resistant HIV-1 Variants in vitro.

Author information

1
Departments of Infectious Diseases and Hematology, Kumamoto University School of Medicine, Kumamoto, 860-8556, Japan.
2
Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
3
Department of Biochemistry, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
4
Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, IN, 47907, USA.
5
Departments of Infectious Diseases and Hematology, Kumamoto University School of Medicine, Kumamoto, 860-8556, Japan. hm21q@nih.gov.
6
Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. hm21q@nih.gov.
7
National Center for Global Health and Medicine Research Institute, Tokyo, 162-8655, Japan. hm21q@nih.gov.

Abstract

We report that GRL-09510, a novel HIV-1 protease inhibitor (PI) containing a newly-generated P2-crown-tetrahydrofuranylurethane (Crwn-THF), a P2'-methoxybenzene, and a sulfonamide isostere, is highly active against laboratory and primary clinical HIV-1 isolates (EC50: 0.0014-0.0028 μM) with minimal cytotoxicity (CC50: 39.0 μM). Similarly, GRL-09510 efficiently blocked the replication of HIV-1NL4-3 variants, which were capable of propagating at high-concentrations of atazanavir, lopinavir, and amprenavir (APV). GRL-09510 was also potent against multi-drug-resistant clinical HIV-1 variants and HIV-2ROD. Under the selection condition, where HIV-1NL4-3 rapidly acquired significant resistance to APV, an integrase inhibitor raltegravir, and a GRL-09510 congener (GRL-09610), no variants highly resistant against GRL-09510 emerged over long-term in vitro passage of the virus. Crystallographic analysis demonstrated that the Crwn-THF moiety of GRL-09510 forms strong hydrogen-bond-interactions with HIV-1 protease (PR) active-site amino acids and is bulkier with a larger contact surface, making greater van der Waals contacts with PR than the bis-THF moiety of darunavir. The present data demonstrate that GRL-09510 has favorable features for treating patients infected with wild-type and/or multi-drug-resistant HIV-1 variants, that the newly generated P2-Crwn-THF moiety confers highly desirable anti-HIV-1 potency. The use of the novel Crwn-THF moiety sheds lights in the design of novel PIs.

PMID:
28947797
PMCID:
PMC5613016
DOI:
10.1038/s41598-017-12052-9
[Indexed for MEDLINE]
Free PMC Article

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