Facile incorporation of urea pseudopeptides into protease substrate analogue inhibitors.
A new procedure that employs a one-pot, oxidative Hofmann rearrangement to incorporate a urea linkage into peptide backbones is detailed herein. This methodology was used to replace the scissile peptide bonds of [Leu5]enkephalin and a hexapeptide HIV-1 protease substrate. The [Leu5]enkephalin analogue was found to inhibit cleavage of hippurylhistidylleucine (HHL) by porcine kidney angiotensin-converting enzyme (PK-ACE) with a 0.88 mM IC50 value, comparable to the Michaelis constant of [Leu5]enkephalin with the same enzyme. The HIV-1 protease substrate analogue was shown to inhibit HIV-1 protease with an IC50=34 microM.
Myers
Adam C
AC
Department of Chemistry, Purdue University West Lafayette, IN 47907-2084, USA.
Kowalski
Jennifer A
JA
Lipton
Mark A
MA
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000737:chemistry; D000818:Animals; D004743:Enkephalin, Leucine / Q000737:chemistry; D016333:HIV Protease / Q000737:chemistry; D015497:HIV-1; D066298:In Vitro Techniques; D007700:Kinetics; D009842:Oligopeptides / Q000737:chemistry*; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship; D013552:Swine; D014508:Urea / Q000737:chemistry*
D000806:Angiotensin-Converting Enzyme Inhibitors; D009842:Oligopeptides; D011480:Protease Inhibitors; C010980:hippuryl-histidyl-leucine; D004743:Enkephalin, Leucine; D014508:Urea; D016333:HIV Protease