Abstract |
A new class of cysteine protease inhibitors based on fumaric acid derived oligopeptides was successfully identified from a high-throughput screening of a solid-phase bound combinatorial library. As target enzymes falcipain and rhodesain were used, which play important roles in the life cycles of the parasites which cause malaria (Plasmodium falciparum) and African sleeping sickness (Trypanosoma brucei rhodesiense). The best inhibitors with unusual amino acid sequences not reported before for this type of enzyme were also fully analyzed in detail in solution. K(i) values in the lower micromolar and even nanomolar region were found. Some inhibitors are even active against plasmodia and show good selectivity relative to other enzymes. Also the mechanism of action was studied and could be shown to be irreversible inhibition.
|
Authors | Uwe Machon, Christian Büchold, Martin Stempka, Tanja Schirmeister, Christoph Gelhaus, Matthias Leippe, Jiri Gut, Philip J Rosenthal, Caroline Kisker, Matthias Leyh, Carsten Schmuck |
Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 52
Issue 18
Pg. 5662-72
(Sep 24 2009)
ISSN: 1520-4804 [Electronic] United States |
PMID | 19715342
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Chemical References |
- Antiprotozoal Agents
- Cysteine Proteinase Inhibitors
- Fumarates
- Peptide Library
- Diamide
- fumaric acid
- Cathepsins
- Cysteine Endopeptidases
- falcipain 2
- rhodesain
- CTSL protein, human
- Cathepsin L
|
Topics |
- Amino Acid Sequence
- Animals
- Antiprotozoal Agents
(chemical synthesis, chemistry, pharmacology)
- Cathepsin L
- Cathepsins
(chemistry)
- Cattle
- Combinatorial Chemistry Techniques
- Cysteine Endopeptidases
(chemistry, metabolism)
- Cysteine Proteinase Inhibitors
(chemical synthesis, chemistry, pharmacology)
- Diamide
(chemistry)
- Drug Evaluation, Preclinical
(methods)
- Fumarates
(chemical synthesis, chemistry, pharmacology)
- Humans
- Peptide Library
- Plasmodium falciparum
(enzymology)
|