Journal Article

JE-2147: A Dipeptide Protease Inhibitor (PI) That Potently Inhibits Multi-PI-Resistant HIV-1

Falloon, Judith, Erickson, John, Kato, Ryohei, Kavlick, Mark F., Ueno, Takamasa, Shintani, Makoto, Yusa, Keisuke, Mitsuya, Hiroaki, Nguyen, Aline, Maroun, Victor, Mimoto, Tsutomu, Yoshimura, Kazuhisa, Masur, Henry, Hayashi, Hideya

1999

Overview

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 IC50 values ranging from 13-41 nM $(<\\text{2-fold changes in IC}_{50}$ 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.

• Publisher: National Academy of Sciences of the United States of America,National Acad Sciences,National Academy of Sciences,The National Academy of Sciences
• Subject: Active sites / Adult / Amino Acid Sequence / Amino acids / Anti-HIV Agents - chemistry / Anti-HIV Agents - pharmacology / Antivirals / Biological Sciences / Cell Line / Cloning, Molecular / Cultured cells / Dipeptides - chemical synthesis / Dipeptides - pharmacology / Drug Design / Drug resistance / Drug Resistance - genetics / Enzymes / HIV / HIV 1 / HIV Protease - chemistry / HIV Protease - genetics / HIV Protease Inhibitors - chemical synthesis / HIV Protease Inhibitors - pharmacology / Human immunodeficiency virus / Human immunodeficiency virus 1 / Human immunodeficiency virus 2 / Humans / Inhibitory concentration 50 / Male / Medical research / Middle Aged / Models, Molecular / Molecular Sequence Data / Molecular Structure / Mutation / Oligopeptides - pharmacology / Phenylbutyrates - chemistry / Phenylbutyrates - pharmacology / Polymerase chain reaction / Protease inhibitors / Proteinase inhibitors / Reverse Transcriptase Inhibitors - pharmacology / Simian immunodeficiency virus / Viruses