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Proc Natl Acad Sci U S A. 2018 Jan 23;115(4):E802-E811. doi: 10.1073/pnas.1717932115. Epub 2017 Dec 26.

From in silico hit to long-acting late-stage preclinical candidate to combat HIV-1 infection.

Author information

1
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520-8066.
2
Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520-8066.
3
Department of Internal Medicine, Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT 06520.
4
Department of Biomedical Engineering, Yale University, New Haven, CT 06511.
5
Department of Chemistry, Yale University, New Haven, CT 06520-8107.
6
Department of Biomedical Engineering, Yale University, New Haven, CT 06511; mark.saltzman@yale.edu priti.kumar@yale.edu william.jorgensen@yale.edu karen.anderson@yale.edu.
7
Department of Internal Medicine, Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT 06520; mark.saltzman@yale.edu priti.kumar@yale.edu william.jorgensen@yale.edu karen.anderson@yale.edu.
8
Department of Chemistry, Yale University, New Haven, CT 06520-8107 mark.saltzman@yale.edu priti.kumar@yale.edu william.jorgensen@yale.edu karen.anderson@yale.edu.
9
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520-8066; mark.saltzman@yale.edu priti.kumar@yale.edu william.jorgensen@yale.edu karen.anderson@yale.edu.

Abstract

The HIV-1 pandemic affecting over 37 million people worldwide continues, with nearly one-half of the infected population on highly active antiretroviral therapy (HAART). Major therapeutic challenges remain because of the emergence of drug-resistant HIV-1 strains, limitations because of safety and toxicity with current HIV-1 drugs, and patient compliance for lifelong, daily treatment regimens. Nonnucleoside reverse transcriptase inhibitors (NNRTIs) that target the viral polymerase have been a key component of the current HIV-1 combination drug regimens; however, these issues hamper them. Thus, the development of novel more effective NNRTIs as anti-HIV-1 agents with fewer long-term liabilities, efficacy on new drug-resistant HIV-1 strains, and less frequent dosing is crucial. Using a computational and structure-based design strategy to guide lead optimization, a 5 µM virtual screening hit was transformed to a series of very potent nanomolar to picomolar catechol diethers. One representative, compound I, was shown to have nanomolar activity in HIV-1-infected T cells, potency on clinically relevant HIV-1 drug-resistant strains, lack of cytotoxicity and off-target effects, and excellent in vivo pharmacokinetic behavior. In this report, we show the feasibility of compound I as a late-stage preclinical candidate by establishing synergistic antiviral activity with existing HIV-1 drugs and clinical candidates and efficacy in HIV-1-infected humanized [human peripheral blood lymphocyte (Hu-PBL)] mice by completely suppressing viral loads and preventing human CD4+ T-cell loss. Moreover, a long-acting nanoformulation of compound I [compound I nanoparticle (compound I-NP)] in poly(lactide-coglycolide) (PLGA) was developed that shows sustained maintenance of plasma drug concentrations and drug efficacy for almost 3 weeks after a single dose.

KEYWORDS:

HIV-1; NNRTI; drug synergy; humanized mice; nanoparticle

PMID:
29279368
PMCID:
PMC5789948
DOI:
10.1073/pnas.1717932115
[Indexed for MEDLINE]
Free PMC Article

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