JE-2147: a dipeptide protease inhibitor (PI) that potently inhibits multi-PI-resistant HIV-1.
We designed, synthesized, and identified JE-2147, an allophenylnorstatine-containing dipeptide HIV protease inhibitor (PI), which is potent against a wide spectrum of HIV-1, HIV-2, simian immunodeficiency virus, and various clinical HIV-1 strains in vitro. Drug-resistant clinical HIV-1 strains, isolated from seven patients who had failed 9-11 different anti-HIV therapeutics after 32-83 months, had a variety of drug-resistance-related amino acid substitutions and were highly and invariably resistant to all of the currently available anti-HIV agents. JE-2147 was, however, extremely potent against all such drug-resistant strains, with IC(50) values ranging from 13-41 nM (<2-fold changes in IC(50) compared with that of wild-type HIV-1). The emergence of JE-2147-resistant HIV-1 variants in vitro was substantially delayed compared with that of HIV-1 resistant to another allophenylnorstatine-containing compound, KNI-272, and other related PIs. Structural analysis revealed that the presence of a flexible P2' moiety is important for the potency of JE-2147 toward wild-type and mutant viruses. These data suggest that the use of flexible components may open a new avenue for designing PIs that resist the emergence of PI-resistant HIV-1. Further development of JE-2147 for treating patients harboring multi-PI-resistant HIV-1 is warranted.
Experimental Retrovirology Section, Medicine Branch, Division of Clinical Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
K
K
Yoshimura
R
R
Kato
K
K
Yusa
M F
MF
Kavlick
V
V
Maroun
A
A
Nguyen
T
T
Mimoto
T
T
Ueno
M
M
Shintani
J
J
Falloon
H
H
Masur
H
H
Hayashi
J
J
Erickson
H
H
Mitsuya
D000328:Adult; D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D003001:Cloning, Molecular; D004151:Dipeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D015195:Drug Design; D004351:Drug Resistance / Q000235:genetics; D016333:HIV Protease / Q000737:chemistry / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009154:Mutation; D009842:Oligopeptides / Q000494:pharmacology; D010654:Phenylbutyrates / Q000737:chemistry / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology
D019380:Anti-HIV Agents; D004151:Dipeptides; D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D010654:Phenylbutyrates; D018894:Reverse Transcriptase Inhibitors; C034940:3-amino-2-hydroxy-4-phenylbutanoic acid; D016333:HIV Protease; C077822:kynostatin 272