Programmed cell death pathways as targets for developing antifilarial drugs: Lessons from the recent findings

Abstract

More than half a century has passed since the introduction of the National Filariasis Control Program; however, as of 2023, lymphatic filariasis (LF) still prevails globally, particularly in the tropical and subtropical regions, posing a substantial challenge to the objective of worldwide elimination. LF is affecting human beings and its economically important livestock leading to a crucial contributor to morbidities and disabilities. The current scenario has been blowing up alarms of attention to develop potent therapeutics and strategies having efficiency against the adult stage of filarial nematodes. In this context, the exploration of a suitable drug target that ensures lethality to macro and microfilariae is now our first goal to achieve. Apoptosis has been the potential target across all three stages of filarial nematodes viz. oocytes, microfilariae (mf) and adults resulting in filarial death after receiving the signal from the reactive oxygen species (ROS) and executed through intrinsic and extrinsic pathways. Hence, it is considered a leading target for developing antifilarial drugs. Herein, we have shown the efficacy of several natural and synthetic compounds/nanoformulations in triggering the apoptotic death of filarial parasites with little or no toxicity to the host body system.

Keywords: ROS; apoptosis; drug development; filariasis; oxidative stress.

FIGURE 1

Schematic representation of the potential efficacy of different chemotherapeutics across the developmental stages of filarial parasites reside in the human host (Wuchereria bancrofti and Onchocerca volvulus), bovine host (Setaria cervi) and rodent host (Acanthocheilonema viteae).

FIGURE 2

Mechanism of apoptosis in filarial parasites. ROS‐induced oxidative stress within the filarial parasites activates a major cell death pathway. EGL‐1 the apoptosis inducer disrupts the normal CED‐4–CED‐9 complex form and makes an association with CED‐9 to create a pro‐apoptotic moiety. Free CED‐4 dimers then oligomerize and make tetrameric apoptosomes with proCED‐3. Activated and cleaved CED‐3 is the ultimate protein responsible for apoptosis in filaria parasites.

FIGURE 3

Apoptosis as a target for developing antifilarial drugs. Apoptosis‐inducing drugs primarily raise oxidative stress inside the parasite body and subsequently activate intrinsic, extrinsic as well as filarial conserved apoptosis pathways, EGL‐1/CED‐9/CED‐4/CED‐3 pathway.

FIGURE 4

Apoptosis as an efficacious target in developing antifilarials in comparison to conventional drug targets.