The new study provides the template for designing new molecules that may play a very important role in the prevention of the malaria pathogenesis.
(Dr. Pawan Malhotra and Dr. Anand Ranganathan)
Malaria is one of the deadliest diseases which give you experiences like fever, chills, and flu-like illness. Despite a gradual decline in the number of malaria cases worldwide, since 2000 the rate of this decline is not encouraging, with nearly half of the world population living in conditions highly susceptible to malaria. A major challenge which scientists and physicians face nowadays is the upsurge of drug-resistant parasites. Indian researchers are looking for alternative drug targets as well as druggable molecules that could be used for targeting such parasites.
In a collaborative effort, Scientists from New Delhi based institutions ICGEB, JNU, and NIPGR- have discovered the new mechanism of parasite invasion process into the RBC and reveals novel targets for the development of drugs against malaria.
The study, published in “Nature Communications,” reveals a novel host-pathogen interaction between human Cyclophilin B and Plasmodium (parasite) PfRhopH3 proteins. Cyclophilin B protein is present on the RBC surface and binds to the PfRhopH3 during the invasion and facilitates the entry of the parasite into the RBC.
In this study, Dr. Ranganathan’s teams have also reported an interaction between Cyclophilin B and another parasite receptor on the RBC (blood cells) surface named as Basigin. Basigin acts as a receptor for the PfRH5 protein of the parasite. “We report that PfRhopH3 and PfRH5 also interact with each other on the parasite surface. Thus, a multi-protein complex involving Human Cyclophilin B and Basigin interacting with parasite proteins PfRhopH3 and PfRh5 respectively- sets the stage for parasite entry in the RBC,” said Dr. Anand Ranganathan. He added, “We also found that Cyclophilin B - PfRhopH3 interaction is crucial for entry of Plasmodium in host cells and inhibiting this interaction can help in inhibiting parasite entry.”
According to the study, Cyclosporin A is a drug that binds to the cyclophilin B and blocks the interaction between Cyclophilin B and PfRhopH3 resulting in the blocking of the invasion process and reduction of the parasite load in the RBCs. “Interestingly, we discovered a long peptide molecule named as CDP3 that efficiently binds to Cyclophilin B. When the efficacy of CDP3 was tested for the prevention of the invasion process, we observed that CDP3 can block the invasion by up to 80%,” said Prem Prakash and Mohammad Zeeshan, first authors of this paper.
“Our study takes us one step ahead in understanding the pathogenesis of malaria and parasite biology at the host-pathogen junction because till now very few host-pathogen interactions have been documented in case of malaria,” said Dr. Pawan Malhotra.
Dr. Ranganathan’s teams have clearly shown that inhibitors of Cyclophilin B and Basigin are able to prevent the invasion of tested P. falciparum strains and it could provide an alternative option for future development of therapeutics.
“Finally, our study provides the template for designing new molecules like CDP3 that may play a very important role during prevention of the malaria pathogenesis,” said Anand Ranganathan about the future perspective of this study.