title: Substrate derived peptidic α-ketoamides as inhibitors of the malarial protease PfSUB1.
abstract: Peptidic α-ketoamides have been developed as inhibitors of the malarial protease PfSUB1. The design of inhibitors was based on the best known endogenous PfSUB1 substrate sequence, leading to compounds with low micromolar to submicromolar inhibitory activity. SAR studies were performed indicating the requirement of an aspartate mimicking the P1' substituent and optimal P1-P4 length of the non-prime part. The importance of each of the P1-P4 amino acid side chains was investigated, revealing crucial interactions and size limitations.
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia.
authors.forename: Samir S
authors.initials: SS
authors.lastname: Kher
authors.affiliation: Division of Parasitology, MRC National Institute for Medical Research, The Ridgeway, Mill, Hill, London NW7 1AA, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Penzo
authors.affiliation: InhibOx Ltd, Oxford Centre for Innovation, New Road, Oxford OX1 1BY, UK.
authors.forename: Simone
authors.initials: S
authors.lastname: Fulle
authors.affiliation: InhibOx Ltd, Oxford Centre for Innovation, New Road, Oxford OX1 1BY, UK.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Finn
authors.affiliation: Division of Parasitology, MRC National Institute for Medical Research, The Ridgeway, Mill, Hill, London NW7 1AA, UK.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Blackman
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia.
authors.forename: Aigars
authors.initials: A
authors.lastname: Jirgensons
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry*; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013381:Subtilisins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000577:Amides; D010455:Peptides; D015800:Protozoan Proteins; D015842:Serine Proteinase Inhibitors; D013381:Subtilisins; C403176:subtilisin-like protease 1, Plasmodium falciparum
keywords: Malaria; Peptides; PfSUB1; Serine protease; α-Ketoamide