Design, synthesis, and biological activities of closantel analogues: structural promiscuity and its impact on Onchocerca volvulus

Area of Science:

• Parasitology
• Drug Discovery
• Biochemistry

Background:

• Onchocerciasis, or river blindness, is a neglected tropical disease affecting over 37 million people globally.
• The larval-stage-specific chitinase, OvCHT1, is identified as a potential therapeutic target for nematode development inhibition.

Purpose of the Study:

• To investigate the anthelmintic drug closantel as a specific inhibitor of OvCHT1.
• To elucidate the mode of action of closantel, including its proton ionophore activity and its impact on O. volvulus larval molting.

Main Methods:

• Screening efforts to identify OvCHT1 inhibitors.
• Investigating the biological activities of closantel and its fragments on O. volvulus L3 molting.
• Structure-activity relationship studies of salicylanilide compounds.

Main Results:

• Closantel was identified as a potent and specific inhibitor of OvCHT1.
• Compounds with solely protonophore or chitinase inhibitory activity were identified using a salicylanilide scaffold.
• Synergistic protonophore and chitinase inhibition were found to be critical for O. volvulus L3 larval molting.

Conclusions:

• OvCHT1 is a viable drug target for onchocerciasis.
• Closantel exhibits a dual mode of action, inhibiting both chitinase and proton transport.
• Targeting both pathways offers a promising strategy for developing new treatments for river blindness.