title: Inhibition of HIV-1 protease by a boron-modified polypeptide.
abstract: Six boronated tetrapeptides with the carboxy moiety of phenylalanine replaced by dihydroxyboron were synthesized, and their activities against human immunodeficiency virus 1 (HIV-1) protease subsequently investigated. The sequences of these peptides were derived from HIV-1 protease substrates, which included the C-terminal part of the scissile bond (Phe-Pro) within the gag-pol polyprotein. Enzymatic studies showed that these compounds were competitive inhibitors of HIV-1 protease with K(i) values ranging from 5 to 18 microM when experiments were performed at high enzyme concentrations (above 5 x 10(-8) M); however, at low protease concentrations inhibition was due in part to an increase of the association constants of the protease subunits. Ac-Thr-Leu-Asn-PheB inhibited HIV-1 protease with a K(i) of 5 microM, whereas the non-boronated parental compound was inactive at concentrations up to 400 microM, which indicates the significance of boronation in enzyme inhibition. The boronated tetrapeptides were inhibitory to an HIV-1 protease variant that is resistant to several HIV-1 protease inhibitors. Finally, fluorescence analysis showed that the interactions between the boronated peptide Ac-Thr-Leu-Asn-PheB and HIV-1 protease resulted in a rapid decrease of fluorescence emission at 360 nm, which suggests the formation of a compound/enzyme complex. Boronated peptides may provide useful reagents for studying protease biochemistry and yield valuable information toward the development of protease dimerization inhibitors.
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06510, USA. pivazya@attglobal.net
authors.forename: A D
authors.initials: AD
authors.lastname: Pivazyan
authors.forename: D S
authors.initials: DS
authors.lastname: Matteson
authors.forename: L
authors.initials: L
authors.lastname: Fabry-Asztalos
authors.forename: R P
authors.initials: RP
authors.lastname: Singh
authors.forename: P F
authors.initials: PF
authors.lastname: Lin
authors.forename: W
authors.initials: W
authors.lastname: Blair
authors.forename: K
authors.initials: K
authors.lastname: Guo
authors.forename: B
authors.initials: B
authors.lastname: Robinson
authors.forename: W H
authors.initials: WH
authors.lastname: Prusoff
mesh_terms: D001896:Boron Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004351:Drug Resistance; D006678:HIV / Q000187:drug effects*; D016333:HIV Protease / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013050:Spectrometry, Fluorescence; D014407:Tumor Cells, Cultured
chemical_list: D001896:Boron Compounds; D017320:HIV Protease Inhibitors; D010455:Peptides; D016333:HIV Protease