@article{ref1,
title="Conus venom fractions inhibit the adhesion of Plasmodium falciparum erythrocyte membrane protein 1 domains to the host vascular receptors",
journal="Journal of Proteomics",
year="2020",
author="Padilla, Alberto and Dovell, Sanaz and Chesnokov, Olga and Hoggard, Mickelene and Oleinikov, Andrew V. and Marí, Frank",
volume="ePub",
number="ePub",
pages="ePub-ePub",
abstract="Using high-throughput BioPlex assays, we determined that six fractions from the venom of Conus nux inhibit the adhesion of various recombinant PfEMP-1 protein  domains (PF08_0106 CIDR1α3.1, PF11_0521 DBL2β3, and PFL0030c DBL3X and DBL5e) to  their corresponding receptors (CD36, ICAM-1, and CSA, respectively). The protein  domain-receptor interactions permit P. falciparum-infected erythrocytes (IE) to  evade elimination in the spleen by adhering to the microvasculature in various  organs including the placenta. The sequences for the main components of the  fractions, determined by tandem mass spectrometry, yielded four T-superfamily  conotoxins, one (CC-Loop-CC) with I-IV, II-III connectivity and three  (CC-Loop-CX(aa)C) with a I-III, II-IV connectivity. The 3D structure for one of the  latter, NuxVA = GCCPAPLTCHCVIY, revealed a novel scaffold defined by double turns  forming a hairpin-like structure stabilized by the two disulfide bonds. Two other  main fraction components were a miniM conotoxin, and a O2-superfamily conotoxin with  cysteine framework VI/VII. This study is the first one of its kind suggesting the  use of conotoxins for developing pharmacological tools for anti-adhesion adjunct  therapy against malaria. Similarly, mitigation of emerging diseases like AIDS and  COVID-19, can also benefit from conotoxins as inhibitors of protein-protein  interactions as treatment. BIOLOGICAL SIGNIFICANCE: Among the 850+ species of cone  snail species there are hundreds of thousands of diverse venom exopeptides that have  been selected throughout several million years of evolution to capture prey and  deter predators. They do so by targeting several surface proteins present in target  excitable cells. This immense biomolecular library of conopeptides can be explored  for potential use as therapeutic leads against persistent and emerging diseases  affecting non-excitable systems. We aim to expand the pharmacological reach of  conotoxins/conopeptides by revealing their in vitro capacity to disrupt  protein-protein and protein-polysaccharide interactions that directly contribute to  pathology of Plasmodium falciparum malaria. This is significant for severe forms of  malaria, which might be deadly even after treated with current parasite-killing  drugs because of persistent cytoadhesion of P. falciparum infected erythrocytes even  when parasites within red blood cells are dead. Anti-adhesion adjunct drugs would  de-sequester or prevent additional sequestration of infected erythrocytes and may  significantly improve survival of malaria patients. These results provide a lead for  further investigations into conotoxins and other venom peptides as potential  candidates for anti-adhesion or blockade-therapies. This study is the first of its  kind and it suggests that conotoxins can be developed as pharmacological tools for  anti-adhesion adjunct therapy against malaria. Similarly, mitigation of emerging  diseases like AIDS and COVID-19, can also benefit from conotoxins as potential  inhibitors of protein-protein interactions as treatment.<p /> <p>Language: en</p>",
language="en",
issn="1874-3919",
doi="10.1016/j.jprot.2020.104083",
url="http://dx.doi.org/10.1016/j.jprot.2020.104083"
}