Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.25.218644v1?rss=1 Authors: Diez-Mejia, A. F., Pedroza, M. M., Orrego, L. M., Pulido, S. A., Echeverry, M. C., Rojas, M., Soares, M. J., Muskus, C. E., Robledo, S. M., Marin-Villa, M., Varela-Miranda, R. E. Abstract: Tritryps are protozoan parasites that belong to the Trypanosomatidae family, which encompasses the etiologic agents of leishmaniasis, African and American trypanosomiasis. These parasites undergo different stress conditions across their life cycle, such as nutritional stress, which needs to be deadened in order to guarantee the survival of the parasite inside its vector and mammal hosts respectively. Here we show that the lack of the serine threonine kinase PKB / AKT-like function, either by allosteric inhibition of its Plekstrin domain (PH) in T. cruzi, the reduction of the gene transcripts in T. brucei by RNAi assays, or by the genomic knockout of its alleles in L. major, causes the parasites to be less tolerant to nutritional stress and promotes apoptosis-like events, including DNA fragmentation, mitochondrial damage and loss of plasma membrane integrity. Additionally, we observed that the Akt-like gene knockout in L. major impairs its infective capacity. This work confirms some of the previously described functions regarding parasite survival for AKT-like kinases in the Leishmania genus. The present work also provides strong evidence of the probable function of Akt-like in T. cruzi and T. brucei survival and infectivity. Author summaryEndemic countries are called to play a paramount role in the discovery of new drug candidates through the application of new drug development strategies, among them the rational drug design method have proven to be compatible with the development of new drug for orphan and neglected diseases since it substantially reduces the costs of discovery and development, a desirable condition for public funded initiatives. Previously we have identified a new parasite protein kinase (AKT-like) as promising new target candidate by means of computational tools and probed its biological role in trypanosomatids. We show that inhibition of the AKT-like kinase in trypanosomatids by different approaches (chemical inhibition, interference RNA and gene knockout) decreases the fitness and survival of the parasites in vitro, interfering with the capacity of the cell to react and survive stress conditions similar to those experienced by the cell in the natural life cycle. Additionally our results strongly supports the potential of a new family of compounds as potential trypanocidal agents previously described by bioinformatic means. Altogether we show here that the specific inhibition of the AKT-like is a promising strategy for the further development of anti-trypanosome drugs. The downstream mechanisms of the observed cellular effects in the ATK pathways is still to be determined and may be the subject of future studies. Copy rights belong to original authors. Visit the link for more info