Towards novel drug targets to counter leishmaniasis infections by leveraging multi-omics data integration and reverse vaccinology approaches? L

LUCAS GENTIL AZEVEDO; EZEQUIEL SOSA; DARÍO FERNÁNDEZ DO PORTO; PABLO IVAN PEREIRA RAMOS

Montevideo

Congreso; Congreso de la Sociedad Iberoamericana de Bioinformática; 2019

Sociedad Iberoamericana de Bioinformática

Leishmaniasis is a disease caused by Leishmania protozoan parasites having multiple manifestations, including cutaneous and visceral. Twelve million people are infected worldwide, with more than 270,000 new cases reported yearly, mainly in poor-income countries. Thus, leishmaniasis is considered one of the most neglected diseases in the world. Vaccines are lacking, and first-line treatment usually employs toxic, non-specific drugs. Few alternative treatment options are under study, and parasite resistance against the current therapies are on the rise. Novel targets that can be further developed into therapeutic options are warranted. Here, we leveraged multi-omics data layers as well as reverse vaccinology approaches1 in order to accelerate the ranking of parasite proteins that meet criteria desirable from a druggability standpoint: expression, essentiality, conservation across various species of pathogenic Leishmania, metabolic importance, druggable structural cavities, and immunogenicity. Host proteins were filtered out using BLASTP against the human proteome. Essentiality data from Toxoplasma gondii available as CRISPR/Cas9 experiments will be propagated to Leishmania from sequence data, as no specific Leishmania experiments are available, and will be enhanced by data from in silico knock-out simulations of an L.infantum metabolic model. The following simple scoring function was developed to rank the parasite proteins using Target Pathogen2:Score=Drg+Imm+Exp+(EssFBA+EssTg)2,nwhich considers structural druggability (Drg), immunogenicity (Imm), expression in amastigote stage (Exp), and essentiality (EssFBA, EssTg). 114,312 parasite proteins present in 14 Leishmania species were retrieved, with 47,221 conserved orthologs, 93% of these having no human similars. Structural models for 4,789 proteins from L.infantum were reconstructed, of which 83% have at least one druggable cavity. Further characterization of these proteins is underway and represents a promising avenue to determine novel candidate targets to tackle Leishmania parasites.