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.

Facile Synthesis of Internal and C‐Terminal Peptide α‐Ketoamides with Fmoc‐Solid Phase Peptide Synthesis

“…Using protected alanine α ‐ketoacid for automated Fmoc solid phase synthesis, we isolated the product in 61% yield with a single purification step by preparative RP‐HPLC. In comparison, the originally reported solution phase route afforded 8 as a mixture of two diastereomers in an overall yield of less than 2% . As another example we prepared HCV protease inhibitor 7 in 22% yield using protected norvaline α ‐ketoacid …”

The Plasmodium berghei serine protease PbSUB1 plays an important role in male gamete egress

“…Several P . falciparum SUB1‐specific inhibitors have been developed (Gemma et al, ; Giovani et al, ; Kher et al, ) and in some cases were shown to be effective in inhibiting parasite emergence from erythrocytes, indicating that SUB1 is a druggable target. In addition, the P .…”

“…SUB1 is already considered a promising drug target for malaria chemotherapy, being essential in both hepatic and asexual blood stages of the Plasmodium life cycle. Several P. falciparum SUB1-specific inhibitors have been developed (Gemma et al, 2012;Giovani et al, 2014;Kher et al, 2014) and in some cases were shown to be effective in inhibiting parasite emergence from erythrocytes, indicating that SUB1 is a druggable target. In addition, the P. falciparum PfSUB1 and Plasmodium vivax PvSUB1 x-ray crystal structures were recently made available (Giganti et al, 2014;Withers-Martinez et al, 2014).…”

In silico study of subtilisin-like protease 1 (SUB1) from different Plasmodium species in complex with peptidyl-difluorostatones and characterization of potent pan-SUB1 inhibitors

“…Endogenous substrates of PfSUB1 have been investigated and some studies analyzing in silico the interaction of peptides based on endogenous sequences with PfSUB1 and PvSUB1 have been previously in depth analyzed [6] , [11] , [16] , [17] , [18] . Few PfSUB1 or PvSUB1 inhibitors have been described to date [11] , [16] , [19] , [20] . We recently developed the first potent difluorostatone-based inhibitors ( 1 and 2 , Fig.…”