A role for the protease falcipain 1 in host cell invasion by the human malaria parasite.
Cysteine proteases of Plasmodium falciparum are required for survival of the malaria parasite, yet their specific cellular functions remain unclear. We used a chemical proteomic screen with a small-molecule probe to characterize the predominant cysteine proteases throughout the parasite life cycle. Only one protease, falcipain 1, was active during the invasive merozoite stage. Falcipain 1-specific inhibitors, identified by screening of chemical libraries, blocked parasite invasion of host erythrocytes, yet had no effect on normal parasite processes such as hemoglobin degradation. These results demonstrate a specific role for falcipain 1 in host cell invasion and establish a potential new target for antimalarial therapeutics.
Greenbaum
Doron C
DC
Department of Pharmaceutical Chemistry, Veterans Affairs Medical Center, University of California, San Francisco, CA 94143, USA. dgreenb@itsa.ucsf.edu
Baruch
Amos
A
Grainger
Munira
M
Bozdech
Zbynek
Z
Medzihradszky
Katlin F
KF
Engel
Juan
J
DeRisi
Joseph
J
Holder
Anthony A
AA
Bogyo
Matthew
M
D000818:Animals; D003546:Cysteine Endopeptidases / Q000302:isolation & purification / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000469:parasitology*; D005455:Fluorescent Antibody Technique; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008018:Life Cycle Stages; D015388:Organelles / Q000201:enzymology; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development / Q000472:pathogenicity*; D040901:Proteomics
D015853:Cysteine Proteinase Inhibitors; D006454:Hemoglobins; D003546:Cysteine Endopeptidases; C099607:falcipain; C416224:falcipain 2; C443101:falcipain 3; D007930:Leucine; C108192:aloxistatin