Identification of phosphinate dipeptide analog inhibitors directed against the Plasmodium falciparum M17 leucine aminopeptidase as lead antimalarial compounds.
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.
Skinner-Adams
Tina S
TS
Malaria Biology Laboratory, Queensland Institute of Medical Research, 300 Herston Road, Herston, Queensland 4029, Australia.
Lowther
Jonathan
J
Teuscher
Franka
F
Stack
Colin M
CM
Grembecka
Jolanta
J
Mucha
Artur
A
Kafarski
Pawel
P
Trenholme
Katharine R
KR
Dalton
John P
JP
Gardiner
Donald L
DL
D000595:Amino Acid Sequence; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D007930:Leucine / Q000031:analogs & derivatives / Q000737:chemistry; D007931:Leucyl Aminopeptidase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010721:Phosphinic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016788:Plasmodium chabaudi / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D013329:Structure-Activity Relationship
D000962:Antimalarials; D004151:Dipeptides; D010721:Phosphinic Acids; D011994:Recombinant Proteins; D007931:Leucyl Aminopeptidase; D007930:Leucine; C012211:ubenimex