Pan-active imidazolopiperazine antimalarials target the Plasmodium falciparum intracellular secretory pathway

Abstract

A promising new compound class for treating human malaria is the imidazolopiperazines (IZP) class. IZP compounds KAF156 (Ganaplacide) and GNF179 are effective against Plasmodium symptomatic asexual blood-stage infections, and are able to prevent transmission and block infection in animal models. But despite the identification of resistance mechanisms in P. falciparum, the mode of action of IZPs remains unknown. To investigate, we here combine in vitro evolution and genome analysis in Saccharomyces cerevisiae with molecular, metabolomic, and chemogenomic methods in P. falciparum. Our findings reveal that IZPresistant S. cerevisiae clones carry mutations in genes involved in Endoplasmic Reticulum (ER)-based lipid homeostasis and autophagy. In Plasmodium, IZPs inhibit protein trafficking, block the establishment of new permeation pathways, and cause ER expansion. Our data highlight a mechanism for blocking parasite development that is distinct from those of standard compounds used to treat malaria, and demonstrate the potential of IZPs for studying ER-dependent protein processing.

Identification and Profiling of a Novel Diazaspiro[3.4]octane Chemical Series Active against Multiple Stages of the Human Malaria Parasite Plasmodium falciparum and Optimization Efforts

“…Mutations in PfCARL typically represent an MoR rather than the MoA or drug target. , Transposon mutagenesis studies recently provided strong evidence that PfCARL is essential . This protein resides in the parasite endoplasmic reticulum where it is suspected to be involved in protein folding, processing, and sorting …”

“…24 This protein resides in the parasite endoplasmic reticulum where it is suspected to be involved in protein folding, processing, and sorting. 25 The amide derivative 1-A displayed superior antiplasmodial activity along with superior margins over cytotoxicity and hERG inhibition relative to the other hit 2-A. As a result, SAR studies that followed were based on 1-A, and the carbonyl group at R 1 was maintained in all of the compounds that were subsequently prepared to mitigate the cardiotoxicity risk.…”

Probing the Open Global Health Chemical Diversity Library for Multistage-Active Starting Points for Next-Generation Antimalarials

“…The higher number of ABS inhibitors versus stage V GAMs is perhaps unsurprising given that relatively few essential pathways are known to exclusively disrupt sexual stage function (such as translation repression, autophagy, or meiosis). Nonetheless, with conserved blood stage targets including protein translation (targeted by puromycin), protein secretion (KAF156), or protein degradation (carmaphycin B and epoxomycin), a higher incidence of dual blood stage inhibitors (versus with either exoerythrocytic form) is more likely. Still, numerous structurally distinct scaffolds with concurrent liver and asexual blood stage activity have been linked to mitochondrial electron transport chain disruption .…”

Deciphering the consequence of deep intronic variants: a progeroid syndrome caused by aTAPT1mutation is revealed by combined RNA/SI-NET sequencing

“…The copyright holder for this preprint this version posted July 21, 2022. ; https://doi.org/10.1101/2022.07. 15.22276800 doi: medRxiv preprint TAPT1 codes for a predicted transmembrane protein which has been related to ER/Golgi pathways, human Cytomegalovirus (HCMV) infection and primary ciliogenesis [9][10][11][12][13][14][15] . Our functional studies using patient derived TAPT1-knockout cells could not detect patent anomalies in the pathways previously linked to TAPT1 indicating that its precise molecular function has yet to be ascertained.…”