Identification of Highly Potent Human Immunodeficiency Virus Type-1 Protease Inhibitors against Lopinavir and Darunavir Resistant Viruses from Allophenylnorstatine-Based Peptidomimetics with P2 Tetrahydrofuranylglycine

Journal of Medicinal Chemistry
Koushi HidakaYoshiaki Kiso

Abstract

The emergence of drug-resistant HIV from a widespread antiviral chemotherapy targeting HIV protease in the past decades is unavoidable and provides a challenge to develop alternative inhibitors. We synthesized a series of allophenylnorstatine-based peptidomimetics with various P3, P2, and P2́ moieties. The derivatives with P2 tetrahydrofuranylglycine (Thfg) were found to be potent against wild type HIV-1 protease and the virus, leading to a highly potent compound 21f (KNI-1657) against lopinavir/ritonavir- or darunavir-resistant strains. Co-crystal structures of 21f and the wild-type protease revealed numerous key hydrogen bonding interactions with Thfg. These results suggest that the strategy to design allophenylnorstatine-based peptidomimetics combined with Thfg residue would be promising for generating candidates to overcome multidrug resistance.

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Citations

Mar 25, 2020·Topics in Current Chemistry·Nusrat SahibaShikha Agarwal
May 1, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Saira HussainChristopher L Blanchard
Jun 28, 2019·Current Medicinal Chemistry·José-Manuel GallyPascal Bonnet
Jul 14, 2021·ChemMedChem·Andrzej S SkwareckiMaria J Milewska
Oct 10, 2019·The Journal of Physical Chemistry. B·Aswathy N MuttathukattilGovardhan Reddy

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