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BioAssay: AID 434965

Summary of the probe development effort to identify inhibitors of the Plasmodium falciparum M17- Family Leucine Aminopeptidase (M17AAP)

Grant Proposal PI: John Dalton and Donald Gardiner, Queensland Institute of Medical Research, Australia ..more
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AID: 434965
Data Source: The Scripps Research Institute Molecular Screening Center (M17LAP_INH_SUMMARY)
BioAssay Type: Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Probe Production Network
BioAssay Version:
Deposit Date: 2010-06-03
Modify Date: 2012-03-14
Target
Depositor Specified Assays
Show more
AIDNameTypeComment
1619Inhibitors of Plasmodium falciparum M17- Family Leucine Aminopeptidase (M17LAP)confirmatoryDose response primary screen (M17LAP inhibitors in triplicate)
2214Counterscreen for inhibitors of M1 and M17 aminopeptidases: QFRET-based biochemical high throughput dose response assay for inhibitors of the Cathepsin L proteinase (CTSL1).confirmatoryDose response counterscreen (CTSL1 inhibitors in triplicate)
2215Counterscreen for inhibitors of M1 and M17 aminopeptidases: QFRET-based biochemical high throughput dose response assay for inhibitors of the Plasmodium falciparum M18 Aspartyl Aminopeptidase (PFM18AAP).confirmatoryDose response counterscreen (PFM18AAP inhibitors in triplicate)
489016Late stage assay provider results from the probe development effort to identify inhibitors of the Plasmodium falciparum M17 Leucine Aminopeptidase (M17LAP): radiolabel-based cell-based dose response assay to identify compounds that inhibit P. falciparum growth in RBCsconfirmatoryLate stage dose response counterscreen (P. falciparum growth inhibitors in triplicate)
492955Late stage assay provider results from the probe development effort to identify inhibitors of the Plasmodium falciparum M17 Leucine Aminopeptidase (M17LAP): radiolabel-based cell-based assay to identify compounds that inhibit P. falciparum growth in RBCsotherLate stage counterscreen (P. falciparum growth inhibitors in triplicate)
492973Late stage assay provider results from the probe development effort to identify inhibitors of the Plasmodium falciparum M7 Leucine Aminopeptidase (PfM17LAP): fluorescence-based biochemical assay to identify inhibitors of malaria cell lysatescreeningLate stage screen (malaria cell lysate in triplicate)
492977Late stage assay provider results from the probe development effort to identify inhibitors of the Plasmodium falciparum M7 Leucine Aminopeptidase (PfM17LAP): fluorescence-based assay to identify inhibitors of rPfM17LAPscreeningLate stage screen (rPfM17LAP inhhibitors in singlicate)
588688QFRET-based biochemical high throughput dose response assay for inhibitors of the Plasmodium falciparum M17 Leucine Aminopeptidase (PFM17LAP)confirmatory
588698Counterscreen for inhibitors of PFM17LAP: QFRET-based biochemical high throughput dose response assay for inhibitors of the Plasmodium falciparum M1AAP (PFM1AAP)confirmatory
588697Counterscreen for inhibitors of PFM17LAP: QFRET-based biochemical high throughput dose response assay for inhibitors of the Plasmodium falciparum M18 Aspartyl Aminopeptidase (PFM18AAP)confirmatory
588707Vero Cytoxicity Assay: A Cell Based Secondary Assay To Explore Cytotoxicity of Compounds that Inhibit Plasmodium falciparum M1 Aspartyl Aminopeptidase (PFM17LAP)confirmatory
602214Counterscreen for inhibitors of PFM17LAP: QFRET-based biochemical high throughput dose response assay for inhibitors of the Human M17LAP (HUM17LAP)confirmatory
602216QFRET-based biochemical high throughput dose response assay for inhibitors of the Plasmodium falciparum M17 Leucine Aminopeptidase (PFM17LAP) (2)confirmatory
602218Counterscreen for inhibitors of PFM17LAP: QFRET-based biochemical high throughput dose response assay for inhibitors of the Plasmodium falciparum M18 Aspartyl Aminopeptidase (PFM18AAP) (2)confirmatory
602223Counterscreen for inhibitors of PFM17LAP: QFRET-based biochemical high throughput dose response assay for inhibitors of the Plasmodium falciparum M1AAP (PFM1AAP) (2)confirmatory
602227Vero Cytoxicity Assay: A Cell Based Secondary Assay To Explore Cytotoxicity of Compounds that Inhibit Plasmodium falciparum M17 Leucine Aminopeptidase (PFM17LAP) (2)confirmatory
602309QFRET-based biochemical high throughput dose response assay for inhibitors of the Plasmodium falciparum M17 Leucine Aminopeptidase (PFM17LAP) (3)confirmatoryMain Screen (M17)
602214Counterscreen for inhibitors of PFM17LAP: QFRET-based biochemical high throughput dose response assay for inhibitors of the Human M17LAP (HUM17LAP)confirmatoryCounterscreen (Human M17)
602315Counterscreen for inhibitors of PFM17LAP: QFRET-based biochemical high throughput dose response assay for inhibitors of the Plasmodium falciparum M1AAP (PFM1AAP) (3)confirmatoryCounterscreen (M1)
602316Counterscreen for inhibitors of PFM17LAP: QFRET-based biochemical high throughput dose response assay for inhibitors of the Plasmodium falciparum M18 Aspartyl Aminopeptidase (PFM18AAP) (3)confirmatoryCounterscreen (M18)
602317Vero Cytoxicity Assay: A Cell Based Secondary Assay To Explore Cytotoxicity of Compounds that Inhibit Plasmodium falciparum M17 Leucine Aminopeptidase (PFM17LAP) (3)confirmatoryCytotoxicity
602407Name: Counterscreen for inhibitors of PFM17LAP: QFRET-based biochemical high throughput dose response assay for inhibitors of the Human M17LAP (HUM17LAP)confirmatory
743273Late stage assay provider results from the probe development effort to identify inhibitors of the Plasmodium falciparum M17 Leucine Aminopeptidase (M17LAP): radiolabel-based cell-based dose response assay to identify compounds that inhibit P. falciparum growth in RBCs Set 2confirmatory
743274Late stage assay provider results from the probe development effort to identify inhibitors of the Plasmodium falciparum M17 Leucine Aminopeptidase (M17LAP): radiolabel-based cell-based assay to identify compounds that inhibit P. falciparum growth in RBCs Set 2screening
Description:
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: M17LAP_INH_SUMMARY

Name: Summary of the probe development effort to identify inhibitors of the Plasmodium falciparum M17- Family Leucine Aminopeptidase (M17AAP).

Description:

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). The intraerythrocytic stages of the human malaria parasite Plasmodium falciparum employs two cytosolic neutral aminopeptidases, an M1-family alanyl aminopeptidase (M1AAP) and an M17-family leucine aminopeptidase (M17LAP), in the terminal stages of host hemoglobin digestion (8, 9). Their action results in the release of free amino acids that are used for the anabolism of parasite proteins and, hence, are critical to the development of the parasite in red blood cells (10, 11). Inhibitors of the two exopeptidases prevent the growth of P. falciparum parasites in vitro, and protect mice from infection with rodent malaria P. chabaudi, providing strong evidence that these enzymes are targets which can be used to develop new anti-malarial drugs (12-14). Thus, Plasmodium falciparum M17-family leucine aminopeptidase (M17LAP) is an attractive chemotherapeutic target and was used to screen a large (200K) chemical library to identify novel inhibitors as probes for this enzyme in Plasmodium falciparum.

Summary of Probe Development Effort:

This probe development effort is focused on the identification of M17LAP inhibitors. All AIDs that contain results associated with this project can be found in the "Related Bioassays" section of this Summary AID.

References:

1. Walling, L.L., Recycling or regulation? The role of amino-terminal modifying enzymes. Curr Opin Plant Biol, 2006. 9(3): p. 227-33.
2. Meinnel, T., Serero, A., and Giglione, C., Impact of the N-terminal amino acid on targeted protein degradation. Biol Chem, 2006. 387(7): p. 839-51.
3. Jankiewicz, U. and Bielawski, W., The properties and functions of bacterial aminopeptidases. Acta Microbiol Pol, 2003. 52(3): p. 217-31.
4. Banegas, I., Prieto, I., Vives, F., Alba, F., de Gasparo, M., Segarra, A.B., Hermoso, F., Duran, R., and Ramirez, M., Brain aminopeptidases and hypertension. J Renin Angiotensin Aldosterone Syst, 2006. 7(3): p. 129-34.
5. Silveira, P.F., Gil, J., Casis, L., and Irazusta, J., Peptide metabolism and the control of body fluid homeostasis. Curr Med Chem Cardiovasc Hematol Agents, 2004. 2(3): p. 219-38.
6. Zhong, H. and Bowen, J.P., Antiangiogenesis drug design: multiple pathways targeting tumor vasculature. Curr Med Chem, 2006. 13(8): p. 849-62.
7. Proost, P., Struyf, S., and Van Damme, J., Natural post-translational modifications of chemokines. Biochem Soc Trans, 2006. 34(Pt 6): p. 997-1001.
8. Stack CM, Lowther J, Cunningham E, Donnelly S, Gardiner DL, Trenholme KR, Skinner-Adams TS, Teuscher F, Grembecka J, Mucha A, Kafarski P, Lua L, Bell A, Dalton JP. 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 Jan 19;282(3):2069-80.
9. Dalal S, Klemba M. J Biol Chem. 2007 Dec 7;282(49):35978-87. Roles for two aminopeptidases in vacuolar hemoglobin catabolism in Plasmodium falciparum. PMID: 17895246
10. Gardiner DL, Trenholme KR, Skinner-Adams TS, Stack CM, Dalton JP. Overexpression of leucyl aminopeptidase in Plasmodium falciparum parasites. Target for the antimalarial activity of bestatin. J Biol Chem. 2006 Jan 20;281(3):1741-5.
11. Curley GP, O'Donovan SM, McNally J, Mullally M, O'Hara H, Troy A, O'Callaghan SA, Dalton JP. Aminopeptidases from Plasmodium falciparum, Plasmodium chabaudi chabaudi and Plasmodium berghei. J Eukaryot Microbiol. 1994 Mar-Apr;41(2):119-23.
12. Skinner-Adams TS, Lowther J, Teuscher F, Stack CM, Grembecka J, Mucha A, Kafarski P, Trenholme KR, Dalton JP, Gardiner DL. Identification of phosphinate dipeptide analog inhibitors directed against the Plasmodium falciparum M17 leucine aminopeptidase as lead antimalarial compounds. J Med Chem. 2007 Nov 29;50(24):6024-31.
13. Gavigan CS, Machado SG, Dalton JP, Bell A. Analysis of antimalarial synergy between bestatin and endoprotease inhibitors using statistical response-surface modelling. Antimicrob Agents Chemother. 2001 Nov;45(11):3175-81.
14. Nankya-Kitaka MF, Curley GP, Gavigan CS, Bell A, Dalton JP.Plasmodium chabaudi chabaudi and P. falciparum: inhibition of aminopeptidase and parasite growth by bestatin and nitrobestatin. Parasitol Res. 1998 Jul;84(7):552-8.

Keywords:

Summary, Summary AID, M17, M17LAP, leucine, leucyl, LAP, aminopeptidase, malaria, parasite, plasmodium falciparum, exopeptidase, dose response, counterscreen, HTS, high throughput screen, 1536, inhibit, inhibitor, inhibition, fluorescence, QFRET, FLINT, peptide, cleavage, Southern, Kansas, KU, Scripps, Scripps Florida, The Scripps Research Institute Molecular Screening Center, SRIMSC, Molecular Libraries Probe Production Centers Network, MLPCN.
Additional Information
Grant Number: 1 R03 MH084103-01

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