title: Synthesis and biological evaluation of modified pentapeptides as potent proteinase K inhibitors.
abstract: This communication reports the first demonstration of synthesis and biological validation of modified pentapeptides, such as methoxysuccinyl-Ala-Ala-Ala-Pro-Leu-chloromethyl ketone 6b as a potent proteinase K inhibitor. The efficacy of MeOSuc-AAAPL-CH(2)Cl 6b analog in inhibiting the proteolytic activity of proteinase K was compared with the known MeOSuc-AAPV-CH(2)Cl analog. The examination of inhibitory activity using RT-PCR assay in the presence of proteinase K revealed that the MeOSuc-AAAPL-CH(2)Cl 6b inhibitor at a concentration of 0.05 mM allows a signal to be obtained for an exogenous target ('Xeno RNA') at 30 cycles (i.e., Ct=30), whereas the control MeOSuc-AAPV-CH(2)Cl requires a fivefold higher concentration (0.25 mM) to produce the same Ct. A plausible explanation for the higher efficiency of MeOSuc-AAAPL-CH(2)Cl 6b over control is proposed based on the molecular modeling studies.
authors.affiliation: Life Technologies Corporation, Bioorganic Chemistry Division, 2130 Woodward Street, Austin, TX 78744-1832, USA. anil.kore@lifetech.com
authors.forename: Anilkumar R
authors.initials: AR
authors.lastname: Kore
authors.forename: Muthian
authors.initials: M
authors.lastname: Shanmugasundaram
authors.forename: Irudaya
authors.initials: I
authors.lastname: Charles
authors.forename: Quoc
authors.initials: Q
authors.lastname: Hoang
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000595:Amino Acid Sequence; D001665:Binding Sites; D019286:Endopeptidase K / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D010455:Peptides; D015842:Serine Proteinase Inhibitors; C550996:methoxysuccinyl-alanyl-alanyl-alanyl-prolyl-leucine chloromethyl ketone; C550997:methoxysuccinyl-alanyl-alanyl-alanyl-prolyl-valine chloromethyl ketone; D019286:Endopeptidase K