Structural Analysis of Potent Hybrid HIV-1 Protease Inhibitors Containing Bis-Tetrahydrofuran in a Pseudo-Symmetric Dipeptide Isostere
Lockbaum, Gordon J.
Rao, Desaboini Nageswara
Nalivaika, Ellen A.
Yilmaz, Nese Kurt
Schiffer, Celia A.
UMass Chan AffiliationsSchiffer Lab
Department of Biochemistry and Molecular Pharmacology
Document TypeAccepted Manuscript
Amino Acids, Peptides, and Proteins
Enzymes and Coenzymes
Medicinal and Pharmaceutical Chemistry
Medicinal Chemistry and Pharmaceutics
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AbstractThe design, synthesis, and X-ray structural analysis of hybrid HIV-1 protease inhibitors (PIs) containing bis-tetrahydrofuran (bis-THF) in a pseudo-C2-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 position on the Phe-Phe isostere. Analyses of cocrystal structures and molecular dynamics simulations provide insights for optimizing HIV-1 PIs containing bis-THF in non-sulfonamide dipeptide isosteres.
Rusere LN, Lockbaum GJ, Henes M, Lee SK, Spielvogel E, Rao DN, Kosovrasti K, Nalivaika EA, Swanstrom R, Kurt Yilmaz N, Schiffer CA, Ali A. Structural Analysis of Potent Hybrid HIV-1 Protease Inhibitors Containing Bis-Tetrahydrofuran in a Pseudo-Symmetric Dipeptide Isostere. J Med Chem. 2020 Jul 16. doi: 10.1021/acs.jmedchem.0c00529. Epub ahead of print. PMID: 32672965. Link to article on publisher's site