1. Structural Analysis of Potent Hybrid HIV-1 Protease Inhibitors Containing Bis-tetrahydrofuran in a Pseudosymmetric Dipeptide Isostere.
- Author
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Rusere LN, Lockbaum GJ, Henes M, Lee SK, Spielvogel E, Rao DN, Kosovrasti K, Nalivaika EA, Swanstrom R, Kurt Yilmaz N, Schiffer CA, and Ali A
- Subjects
- Crystallography, X-Ray, Darunavir analogs & derivatives, Darunavir pharmacology, Dipeptides chemistry, Dipeptides pharmacology, Drug Design, HEK293 Cells, HIV Infections drug therapy, HIV Infections virology, HIV Protease chemistry, HIV-1 drug effects, Humans, Models, Molecular, Structure-Activity Relationship, Furans chemistry, Furans pharmacology, HIV Protease metabolism, HIV Protease Inhibitors chemistry, HIV Protease Inhibitors pharmacology, HIV-1 enzymology
- Abstract
The design, synthesis, and X-ray structural analysis of hybrid HIV-1 protease inhibitors (PIs) containing bis-tetrahydrofuran (bis-THF) in a pseudo-C
2 -symmetric dipeptide isostere are described. A series of PIs were synthesized by incorporating bis-THF of darunavir on either side of the Phe-Phe isostere of lopinavir in combination with hydrophobic amino acids on the opposite P2/P2' position. Structure-activity relationship studies indicated that the bis-THF moiety can be attached at either the P2 or P2' position without significantly affecting potency. However, the group on the opposite P2/P2' position had a dramatic effect on potency depending on the size and shape of the side chain. Cocrystal structures of inhibitors with wild-type HIV-1 protease revealed that the bis-THF moiety retained similar interactions as observed in the darunavir-protease complex regardless of the position on the Phe-Phe isostere. Analyses of cocrystal structures and molecular dynamics simulations provide insights into optimizing HIV-1 PIs containing bis-THF in non-sulfonamide dipeptide isosteres.- Published
- 2020
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