Roger A. Smith

Synthesis and activity of conformationally-constrained macrocyclic norstatine-based inhibitors of HIV protease

Abstract Two diastereomers of a macrocyclic hydroxyamide (norstatine-based) peptide, having an 18-membered ring system, have been synthesized as HIV protease inhibitors. The (R)-diastereomer (IC50 19 nM) was ∼17-fold weaker than an acyclic analog, but had comparable or better antiviral activity, suggesting improved cell penetration properties and/or resistance to cellular enzymes for the macrocyclic inhibitor.

Carbon-13 NMR characterization of the papain adduct formed by peptidyl acyloxy-, aryloxy-, and chloromethyl ketone irreversible inhibitors

Abstract N -Benzyloxycarbonyl- l -phenylalanyl-glycine-derived mesitoyloxy- and pentafluorophenoxymethyl ketones, incorporating carbon-13 labels at the ketone carbonyl and α-keto methylene positions, were synthesized. These compounds act as quiescent affinity labels of cysteine proteinases. NMR studies have established that these compounds form an irreversible covalent adduct with papain, via release of mesitoic acid or pentafluorophenol. The same adduct was formed in each case, with 13 C NMR signals at 214.7 ppm ( C OCH 2 ) and 38.1 ppm (CO C H 2 ). Identical spectra were observed for the adduct formed from the analogous 13 C-labeled chloromethyl ketones; the structure of this type of adduct has been previously established by X-ray studies. Our NMR data are consistent with this structure, and provide a sensitive measure of the hydrogen-bonding to the P 1 carbonyl. Disruption of this hydrogen-bonding by denaturation produced a 13 C NMR shift of 10 ppm to higher field in the carbonyl carbon, to a chemical shift in accordance with that of a model thiomethyl ketone.

Design, synthesis, and activity of conformationally-constrained macrocyclic peptide-based inhibitors of HIV protease

Abstract Conformationally-constrained macrocyclic peptide-based hydroxyethylamines, with 17- to 19-membered ring systems, have been designed and synthesized as HIV protease inhibitors. Structure-activity relationships were consistent with molecular modeling studies, and certain cyclic inhibitors were developed with HIV protease IC50 values of ∼1 nM, and antiviral activities (HIV-1/RF infected MT-2 cells) of EC50 4–8 nM.