Researchers from the International Centre for Genetic Engineering and Biotechnology (ICGEB), Delhi have found a novel route to discover new drug targets and potential drugs for parasites such as Loa loa nematode (roundworm) and Schistosoma mansoni platyhelminths (flatworm) that cause several diseases. The results were published in the journal PLOS Neglected Tropical Diseases .
Both these parasites are the cause of major health burden, particularly in African countries. There are limited treatment options and there is the threat of drug resistance. There also little interest in developing drugs for these diseases by pharmaceutical companies as they do not stand to benefit much commercially.
Instead of blindly screening molecules, which takes a long time and is expensive, a team led by Dr. Amit Sharma from the Molecular Medicine Group at ICGEB looked at Aminoacyl-tRNA synthetases (aaRSs) of the two parasites.
The aaRSs are vital enzymes that decode genetic information and enable protein translation. “The reason why we chose the tRNA synthetase enzyme family is because it is highly conserved [genomic similarity] in malaria and other parasites, including L loa and S. mansoni,” said Dr. Sharma, the corresponding author of the paper. The novel approach of looking at the conserved region of the parasites is direct, quicker and cheaper.
The aaRSs enzyme family has 20 members and each one of the enzymes contributes to protein synthesis. Even if one of the 20 enzymes is missing then protein synthesis cannot happen. “We have elaborated all the critical aaRs enzymes that contribute to protein synthesis,” he said.
In a next step, the team picked up one of the enzymes and validated it as a drugable target.
For that purpose, the enzymes were recombinantly produced and their activities were studied. “Cladosporin, a very potent compound that targets the malaria parasite in both blood and liver stages, seems to inhibit the enzymes of the L. loa and S. mansoni with high potency,” Dr. Sharma said.
The researchers studied the crystal structure of the enzyme with cladosporin. This revealed how tightly the drug binds within the active site of the enzyme.
The researchers could understand the active sites of the enzyme and how the drug inhibits their enzyme activity.