RT Journal Article SR Electronic T1 AKT-like kinase promotes cell survival during nutritional stress in tripanosomatids JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.07.25.218644 DO 10.1101/2020.07.25.218644 A1 Andrés Felipe Díez Mejía A1 María Magdalena Pedroza A1 Lina M. Orrego A1 Sergio Andrés Pulido Muñoz A1 María Clara Echeverry A1 Mauricio Rojas A1 Maurilio José Soares A1 Carlos Enrique Muskus A1 Sara María Robledo A1 Marcel Marín-Villa A1 Rubén E. Varela-Miranda YR 2020 UL http://biorxiv.org/content/early/2020/07/25/2020.07.25.218644.abstract AB 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 summary Endemic 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.Competing Interest StatementThe authors have declared no competing interest.