Expanding the repertoire of DAF-12 ligands: discovery of steroid-based small molecules that modulate life cycle and lifespan of C. elegans

GOLA GABRIEL; SEGOBIA VICTORIA; GALILEA AGUSTÍN; RAMÍREZ JAVIER; SANTILLAN VANESSA; ALVAREZ LAUTARO; CASTRO OLGA

Rosario

Congreso; 2nd Latin American Worm Meeting; 2020

CONICET

Steroids have a long history in human and animal pharmacology and syntheticanalogues are now widely used in many chemical therapies. The appearance ofresistance to anthelmintic drugs is a major problem in the global fight against parasiticnematodes infecting humans, animals and plants. Finding new therapeutic targets anddrugs for treating parasitic infections is an urgent issue. The discovery that the life cycleof nematodes is also controlled by steroids has sparked the idea of using them as thebasis for treating a spectrum of parasitic diseases. In this work, we show, for the firsttime, the feasibility of expanding the repertoire of ligands for the nuclear receptor DAF12 of C. elegans (CeDAF-12), which has been proposed as relevant therapeutic target,by designing structurally diverse steroid-derived small molecules that are able tomodulate its life cycle and lifespan. These compounds were obtained by a modularsynthesis strategy based on the Ugi multicomponent reaction allowing further structuraloptimization and achieved stable binding poses according to docking and MolecularDynamics studies. We screened the synthetized compounds library and identifiedcompounds that showed agonistic or antagonistic activity towards CeDAF-12 using cellbased reporter and in vivo assays. Wild type worms treated with antagonisticcompounds were 15-30 % bigger than untreated ones, accumulated lipids and showedan extended lifespan. Daf-c mutants recovered from diapause in presence of agonisticcompounds reaching different stages of development. These results opens thepossibility of expanding the collection of compounds to be tested for anthelmintic activityand also used as chemical tools for studying C.elegans life cycle and lifespan.