Summary of probe development efforts to identify inhibitors of the Plasmodium falciparum M18 Aspartyl Aminopeptidase (M18AAP)
Grant Proposal PI: John Dalton and Donald Gardiner, Queensland Institute of Medical Research, Australia ..more
Source (MLPCN Center Name): The Scripps Research Institute Molecular Screening Center
Affiliation: The Scripps Research Institute, TSRI
Assay Provider: John Dalton and Donald Gardiner, Queensland Institute of Medical Research, Australia
Network: Molecular Library Probe Production Centers Network (MLPCN)
Grant Proposal Number 1 R03 MH084103-01
Grant Proposal PI: John Dalton and Donald Gardiner, Queensland Institute of Medical Research, Australia
External Assay ID: M18AAP_INH_ LEADS_SUMMARY
Name: Summary of probe development efforts to identify inhibitors of the Plasmodium falciparum M18 Aspartyl Aminopeptidase (M18AAP)
Aminopeptidases (APs) are metalloproteases that cleave amino-terminal (N-terminal) amino acids during protein synthesis (1, 2) These enzymes are characterized in part by their post-translational removal of leucine, aspartate, proline, methionine, etc from proteins and peptides, in order that proteins are properly regulated, targeted for degradation, and trafficked within both animal and plant cells (3). As a result, these enzymes are involved in diverse processes, including meiosis (1), cellular senescence (1), blood pressure control (4, 5), angiogenesis (6), and inflammation (7). PfM18AAP is the sole aspartyl aminopeptidase (AAP) present in the genome of the malaria parasite Plasmodium falciparum (8). It exhibits exopeptidase activity exclusively against the N-terminal acidic amino acids glutamate and aspartate (9-11), is found in all intra-erythrocyte stages of the parasite (9), and functions to complete the hydrolysis of host hemoglobin to amino acids for use in de novo protein synthesis by the parasite (12, 13). Studies demonstrating that genetic knockdown of PfM18AAP results in a lethal parasite phenotype (9), and that inhibitors of methionine (14) and leucine (12, 15) aminopeptidases prevent malaria growth in culture and hemoglobin degradation, suggest that these enzymes are essential for parasite survival. As a result, the identification of selective inhibitors of PfM18AAP would elucidate this enzyme's role in the P. falciparum lifecycle, and serve as potential therapeutic agents to control malaria infection.
Summary of Probe Development Effort:
Following primary HTS in singlicate to identify PFM18AAP inhibitors (AID 1822), certain compounds were identified as possible candidates for probe development. A probe development effort is currently underway at the SRIMSC.
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15. Stack, C.M., Lowther, J., Cunningham, E., Donnelly, S., Gardiner, D.L., Trenholme, K.R., Skinner-Adams, T.S., Teuscher, F., Grembecka, J., Mucha, A., Kafarski, P., Lua, L., Bell, A., and Dalton, J.P., Characterization of the Plasmodium falciparum M17 leucyl aminopeptidase. A protease involved in amino acid regulation with potential for antimalarial drug development. J Biol Chem, 2007. 282(3): p. 2069-80.
Summary AID, Aspartyl aminopeptidase, PfM18AAP, M18AAP, rPfAAP, malaria, parasite, plasmodium falciparum, exopeptidase, primary screen, HTS, high throughput screen, 1536, inhibitor, fluorescence, peptide, cleavage, Scripps, Scripps Florida, The Scripps Research Institute Molecular Screening Center, SRIMSC, Molecular Libraries Probe Production Centers Network, MLPCN.