Malar Res Treat. 2014;2014:642391. doi: 10.1155/2014/642391. Epub 2014 Dec 18.

Bioinformatic Identification of Peptidomimetic-Based Inhibitors against Plasmodium falciparum Antigen AMA1.

Malaria research and treatment

Asrar Alam

PMID: 25580351 PMCID: PMC4281401 DOI: 10.1155/2014/642391

Abstract

Plasmodium falciparum apical membrane antigen 1 (PfAMA1) is a valuable vaccine candidate and exported on the merozoite surface at the time of erythrocyte invasion. PfAMA1 interacts with rhoptry neck protein PfRON2, a component of the rhoptry protein complex, which forms the tight junction at the time of invasion. Phage display studies have identified a 15-residue (F1) and a 20-residue (R1) peptide that bind to PfAMA1 and block the invasion of erythrocytes. Cocrystal structures of central region of PfAMA1 containing disulfide-linked clusters (domains I and II) with R1 peptide and a peptide derived from PfRON2 showed strong structural similarity in binding. The peptides bound to a hydrophobic groove surrounded by domain I and II loops. In this study, peptidomimetics based on the crucial PfAMA1-binding residues of PfRON2 peptide have been identified. Top 5 peptidomimetics when checked for their docking on the region of PfAMA1 encompassing the hydrophobic groove were found to dock on the groove. Drug-like molecules having structural similarity to the top 5 peptidomimetics were identified based on their binding ability to PfAMA1 hydrophobic groove in blind docking. These inhibitors provide potential lead compounds, which could be used in the development of antimalarials targeting PfAMA1.

References

1. PLoS Pathog. 2011 Feb 10;7(2):e1001282 - PubMed
2. Infect Immun. 2000 May;68(5):2899-906 - PubMed
3. Mol Biochem Parasitol. 1994 Sep;67(1):59-68 - PubMed
4. IUBMB Life. 2010 Oct;62(10):724-31 - PubMed
5. J Biol Chem. 1998 Jun 12;273(24):15119-24 - PubMed
6. Infect Immun. 2005 Oct;73(10):6981-9 - PubMed
7. Mol Microbiol. 2000 Nov;38(4):706-18 - PubMed
8. J Mol Biol. 2002 Sep 27;322(4):741-53 - PubMed
9. Science. 2005 Apr 15;308(5720):408-11 - PubMed
10. Proc Natl Acad Sci U S A. 2011 Aug 9;108(32):13275-80 - PubMed
11. Nucleic Acids Res. 2012 Jul;40(Web Server issue):W288-93 - PubMed
12. Infect Immun. 2002 Aug;70(8):4471-6 - PubMed
13. Biochemistry. 2003 Aug 26;42(33):9915-23 - PubMed
14. J Biol Chem. 2002 Dec 27;277(52):50303-10 - PubMed
15. J Biol Chem. 2010 May 7;285(19):14815-22 - PubMed
16. PLoS Pathog. 2009 Feb;5(2):e1000309 - PubMed
17. Science. 2003 Sep 12;301(5639):1503-8 - PubMed
18. Infect Immun. 2001 May;69(5):3286-94 - PubMed
19. Mol Microbiol. 2004 Apr;52(1):159-68 - PubMed
20. J Cell Sci. 2003 Sep 15;116(Pt 18):3825-34 - PubMed
21. J Biol Chem. 1996 Nov 15;271(46):29446-52 - PubMed
22. Vaccine. 1998 Jan-Feb;16(2-3):240-7 - PubMed
23. J Comput Chem. 2010 Jan 30;31(2):455-61 - PubMed
24. J Biol Chem. 2001 Aug 17;276(33):31311-20 - PubMed
25. Nat Commun. 2013;4:2261 - PubMed
26. Proc Natl Acad Sci U S A. 1999 Feb 16;96(4):1167-9 - PubMed
27. PLoS Pathog. 2011 Feb 10;7(2):e1001276 - PubMed
28. Adv Drug Deliv Rev. 2001 Mar 1;46(1-3):3-26 - PubMed
29. PLoS Pathog. 2012;8(6):e1002755 - PubMed
30. Infect Immun. 2002 Dec;70(12):6961-7 - PubMed
31. Nucleic Acids Res. 2011 Jul;39(Web Server issue):W261-9 - PubMed
32. Parasite Immunol. 1988 Sep;10(5):535-52 - PubMed
33. Proc Natl Acad Sci U S A. 2005 Sep 6;102(36):12736-41 - PubMed
34. Mol Biochem Parasitol. 2001 Apr 6;113(2):279-87 - PubMed
35. Proc Natl Acad Sci U S A. 1998 Feb 3;95(3):1230-5 - PubMed
36. Mol Biochem Parasitol. 1995 Apr;71(1):99-113 - PubMed
37. J Biol Chem. 1990 Oct 15;265(29):17974-9 - PubMed
38. Mol Cell Biol. 1989 Jul;9(7):3151-4 - PubMed

Publication Types

• Journal Article