Identification of phosphinate dipeptide analog inhibitors directed against the Plasmodium falciparum M17 leucine aminopeptidase as lead antimalarial compounds.
J Med Chem
; 50(24): 6024-31, 2007 Nov 29.
Article
em En
| MEDLINE
| ID: mdl-17960925
ABSTRACT
Previous studies have pinpointed the M17 leucyl aminopeptidase of Plasmodium falciparum (PfLAP) as a target for the development of new antimalarials. This metallo-exopeptidase functions in the terminal stages of hemoglobin digestion and is inhibited by bestatin, a natural analog of Phe-Leu. By screening novel phosphinate dipeptide analogues for inhibitory activity against recombinant PfLAP, we have discovered two compounds, 4 (hPheP[CH2]Phe) and 5 (hPheP[CH2]Tyr), with inhibitory constants better than bestatin. These compounds are fast, tight-binding inhibitors that make improved contacts within the active site of PfLAP. Both compounds inhibit the growth of P. falciparum in vitro, exhibiting IC50 values against the chloroquine-resistant clone Dd2 of 20-40 and 12-23 muM, respectively. While bestatin exhibited some in vivo activity against Plasmodium chabaudi chabaudi, compound 4 reduced parasite burden by 92%. These studies establish the PfLAP as a prime target for the development of antimalarial drugs and provide important new lead compounds.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ácidos Fosfínicos
/
Plasmodium falciparum
/
Dipeptídeos
/
Leucil Aminopeptidase
/
Antimaláricos
Tipo de estudo:
Diagnostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2007
Tipo de documento:
Article