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Steffey, Melinda

Publications and source records attributed to Steffey, Melinda.

5 records
All sourcesNASA NTRSDOE OSTI
DOE OSTI2017

Design, Synthesis, Biological Evaluation, and X-ray Studies of HIV-1 Protease Inhibitors with Modified P2' Ligands of Darunavir

The structure–based design, synthesis, and biological evaluation of a series of nonpeptidic HIV–1 protease inhibitors with rationally designed P2' ligands are described. The inhibitors are designed to enhance backbone binding interactions, particularly at the S2' subsite. Synthesis of inhibitors was carried out efficiently. The stereochemistry of alcohol functionalities of the P2' ligands was set by asymmetric reduction of the corresponding ketone using (R,R)– or (S,S)–Noyori catalysts. A number of inhibitors displayed very potent enzyme inhibitory and antiviral activity. Inhibitors 3g and 3h showed enzyme Ki values of 27.9 and 49.7 pm and antiviral activity of 6.2 and 3.9 nm, respectively. These inhibitors also remained quite potent against darunavir–resistant HIV–1 variants. In conclusion, an X–ray structure of inhibitor 3g in complex with HIV–1 protease revealed key interactions in the S2' subsite.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2017

Design, synthesis, X-ray studies, and biological evaluation of novel macrocyclic HIV-1 protease inhibitors involving the P1'-P2' ligands

Design, synthesis, and evaluation of a new class of HIV-1 protease inhibitors containing diverse flexible macrocyclic P1'-P2' tethers are reported. Inhibitor 5a with a pyrrolidinone-derived macrocycle exhibited favorable enzyme inhibitory and antiviral activity (K i = 13.2 nM, IC 50 = 22 nM). Further incorporation of heteroatoms in the macrocyclic skeleton provided macrocyclic inhibitors 5m and 5o. Lastly, these compounds showed excellent HIV-1 protease inhibitory (K i = 62 pM and 14 pM, respectively) and antiviral activity (IC 50 = 5.3 nM and 2.0 nM, respectively). Inhibitor 5o also remained highly potent against a DRV-resistant HIV-1 variant.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Design, synthesis, biological evaluation and X-ray structural studies of HIV-1 protease inhibitors containing substituted fused-tetrahydropyranyl tetrahydrofuran as P2-ligands

Design, synthesis, biological and X-ray crystallographic studies of a series of potent HIV-1 protease inhibitors are described. Various polar functionalities have been incorporated on the tetrahydropyranyl-tetrahydrofuran-derived P2 ligand to interact with the backbone atoms in the S2-subsite. Here, the majority of the inhibitors showed very potent enzyme inhibitory and antiviral activity. Two high-resolution X-ray structures of 30b- and 30j-bound HIV-1 protease provide insight into ligand-binding site interactions. In particular, the polar functionalities on the P2-ligand appear to form unique hydrogen bonds with Gly48 amide NH and amide carbonyl groups in the flap region.

59 BASIC BIOLOGICAL SCIENCES↗