title: Design, synthesis, and biological evaluation of HIV/FIV protease inhibitors incorporating a conformationally constrained macrocycle with a small P3' residue.
abstract: A series of norstatine-based HIV/FIV protease inhibitors incorporating a 15-membered macrocycle as a mimic of the tripeptide (Ala-Val-Phe), a motif with a small P3' residue elective against the FIV protease and the drug-resistant HIV proteases, has been synthesized. It was found that the macrocycle is important to the overall activity of the inhibitors. Certain inhibitors were developed expressing low nanomolar inhibitory activity against the HIV/FIV proteases and they are also effective against some drug-resistant as well as TL3-resistant HIV proteases.
authors.affiliation: Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: C C
authors.initials: CC
authors.lastname: Mak
authors.forename: V D
authors.initials: VD
authors.lastname: Le
authors.forename: Y C
authors.initials: YC
authors.lastname: Lin
authors.forename: J H
authors.initials: JH
authors.lastname: Elder
authors.forename: C H
authors.initials: CH
authors.lastname: Wong
mesh_terms: D020816:Amino Acid Motifs; D000614:Aminocaproates / Q000737:chemistry; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D004351:Drug Resistance; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D016089:Immunodeficiency Virus, Feline / Q000201:enzymology; D020128:Inhibitory Concentration 50; D008968:Molecular Conformation; D018716:Molecular Mimicry; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000614:Aminocaproates; D000998:Antiviral Agents; D017320:HIV Protease Inhibitors; D010456:Peptides, Cyclic; D011480:Protease Inhibitors; C034495:3-amino-2-hydroxy-5-methylhexanoic acid; D016282:Aspartic Acid Endopeptidases; C095555:FIV protease