Paper Citing NAMD - Abstract
Kanodia, Shivani; Kumar, Gautam; Rizzi, Luca; Pedretti, Alessandro; Hodder, Anthony N.; Romeo, Sergio; Malhotra, Pawan
Synthetic peptides derived from the C-terminal 6 kDa region of Plasmodium falciparum SERA5 inhibit the enzyme activity and malaria parasite development
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS, 1840:2765-2775, SEP 2014
Background: Plasmodium falciparum serine repeat antigen 5 (PfSERA5) is an abundant blood stage protein that plays an essential role in merozoite egress and invasion. The native protein undergoes extensive proteolytic cleavage that appears to be tightly regulated. PfSERA5 N-terminal fragment is being developed as vaccine candidate antigen. Although PfSERA5 belongs to papain-like cysteine protease family, its catalytic domain has a serine in place of cysteine at the active site. Methods: In the present study, we synthesized a number of peptides from the N- and C-terminal regions of PfSERA5 active domain and evaluated their inhibitory potential. Results: The final proteolytic step of PfSERA5 involves removal of a C-terminal similar to 6 kDa fragment that results in the generation of a catalytically active similar to 50 kDa enzyme. In the present study, we demonstrate that two of the peptides derived from the C-terminal similar to 6 kDa region inhibit the parasite growth and also cause a delay in the parasite development. These peptides reduced the enzyme activity of the recombinant protein and co-localized with the PfSERA5 protein within the parasite, thereby indicating the specific inhibition of PfSERA5 activity. Molecular docking studies revealed that the inhibitory peptides interact with the active site of the protein. Interestingly, the peptides did not have an effect on the processing of PfSERA5. Conclusions: Our observations indicate the temporal regulation of the final proteolytic cleavage step that occurs just prior to egress. General significance: These results reinforce the role of PfSERA5 for the intra-erythrocytic development of malaria parasite and show the role of carboxy terminal similar to 6 kDa fragments in the regulation of PfSERA5 activity. The results also suggest that final cleavage step of PfSERA5 can be targeted for the development of new anti-malarials. (C) 2014 Elsevier B.V. All rights reserved.
