Wolbachia Ferrochelatase as a potential drug target against filarial infections

by Selleckchem | Jun 16 2023

Filarial infections are among the world's most disturbing diseases caused by 3 major parasitic worms; Onchocerca volvulus, Wuchereria bancrofti, and Brugia malayi, affecting more than 500 million people worldwide. Currently used drugs for mass drug administration (MDA) have been met with several challenges including the development of complications in individuals with filaria co-infections and parasitic drug resistance. The filarial endosymbiont, Wolbachia, has emerged as an attractive therapeutic target for filariasis elimination, due to the dependence of the filaria on this endosymbiont for survival. Here, we target an important enzyme in the Wolbachia heme biosynthetic pathway (ferrochelatase), using high-throughput virtual screening and molecular dynamics with MM-PBSA calculations. We identified four drug candidates; Nilotinib, Ledipasvir, 3-benzhydryloxy-8-methyl-8-azabicyclo[3.2.1]octane, and 2-(4-Amino-piperidin-1-yl)-ethanol as potential small molecules inhibitors as they could compete with the enzyme's natural substrate (Protoporphyrin IX) for active pocket binding. This prevents the worm from receiving the heme molecule from Wolbachia for their growth and survival, resulting in their death. This study which involved targeting enzymes in biosynthetic pathways of the parasitic worms' endosymbiont (Wolbachia), has proven to be an alternative therapeutic option leading to the discovery of new drugs, which will help facilitate the elimination of parasitic infections.

Comments:

The description highlights an interesting approach to combating filarial infections, a group of diseases caused by parasitic worms that affect a significant number of people worldwide. The use of current drugs for mass drug administration (MDA) has encountered challenges, including complications in individuals with filaria co-infections and the development of parasitic drug resistance.

The focus on Wolbachia, a symbiotic bacterium present in the filarial worms, as a therapeutic target is promising. The filarial worms rely on Wolbachia for their survival, making it an attractive target for elimination strategies. By targeting an essential enzyme, ferrochelatase, in Wolbachia's heme biosynthetic pathway, researchers have identified potential drug candidates using high-throughput virtual screening and molecular dynamics simulations with MM-PBSA calculations.

The four identified drug candidates, Nilotinib, Ledipasvir, 3-benzhydryloxy-8-methyl-8-azabicyclo[3.2.1]octane, and 2-(4-Amino-piperidin-1-yl)-ethanol, have shown potential as small molecule inhibitors. They can compete with the enzyme's natural substrate, Protoporphyrin IX, for binding in the active pocket. This interference prevents the worms from receiving the heme molecule from Wolbachia, ultimately leading to their death and inhibiting their growth and survival.

This study represents an alternative therapeutic option for filarial infections by targeting enzymes in the biosynthetic pathways of the endosymbiont, Wolbachia. By disrupting the relationship between the worms and Wolbachia, new drugs can be developed to aid in the elimination of these parasitic infections.