Unveiling the kinomes of leishmania infantum and L. braziliensis empowers the discovery of new kinase targets and antileishmanial compounds

Leishmaniasis is a neglected tropical disease caused by parasites of the genus Leishmania (NTD) endemic in 98 countries. Although some drugs are available, current treatments deal with issues such as toxicity, low efficacy, and emergence of resistance. Therefore, there is an urgent need to identify new targets for the development of new antileishmanial drugs. Protein kinases (PKs), which play an essential role in many biological processes, have become potential drug targets for many parasitic diseases. A refined bioinformatics pipeline was applied in order to define and compare the kinomes of L. infantum and L. braziliensis, species that cause cutaneous and visceral manifestations of leishmaniasis in the Americas, the latter being potentially fatal if untreated. Respectively, 224 and 221 PKs were identified in L. infantum and L. braziliensis overall. Almost all unclassified eukaryotic PKs were assigned to six of nine major kinase groups and, consequently, most have been classified into family and subfamily. Furthermore, revealing the kinomes for both Leishmania species allowed for the prioritization of potential drug targets that could be explored for discovering new drugs against leishmaniasis. Finally, we used a drug repurposing approach and prioritized seven approved drugs and investigational compounds to be experimentally tested against Leishmania. Trametinib and NMS-1286937 inhibited the growth of L. infantum and L. braziliensis promastigotes and amastigotes and therefore might be good candidates for the drug repurposing pipeline17352361FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE GOIÁS - FAPE

Unveiling the Kinomes of Leishmania infantum and L. braziliensis Empowers the Discovery of New Kinase Targets and Antileishmanial Compounds

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2019-04-09T16:22:10Z No. of bitstreams: 1 Borba J. Unveiling the kinomes...2019.pdf: 604364 bytes, checksum: bc42a4406b1398d770853cd73c27becf (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2019-04-09T16:40:32Z (GMT) No. of bitstreams: 1 Borba J. Unveiling the kinomes...2019.pdf: 604364 bytes, checksum: bc42a4406b1398d770853cd73c27becf (MD5)Made available in DSpace on 2019-04-09T16:40:32Z (GMT). No. of bitstreams: 1 Borba J. Unveiling the kinomes...2019.pdf: 604364 bytes, checksum: bc42a4406b1398d770853cd73c27becf (MD5) Previous issue date: 2019CNPq, CAPES, and FAPEG for fellowships and funding this work. E.N.M. appreciate support from NIH (grant 1U01CA207160) and CNPq (grant 400760/2014-2). NF is supported by the Medical Research Council (grantMR/K020420/1). DCM is a recipient of a young investigator award from FAPESP (2014/21129-4). CHA has a research fellow in productivity of CNPq. CHA also thanks the “L'Oréal-UNESCOABC Para Mulheres na Ciência” and “L'Oréal-UNESCO International Rising Talents” for the awards and fellowships received, which partially funded thiswork. Additionally, JVBB and ACSwere supported by fellowships from CAPES.Universidade Federal de Goiás. Faculdade de Farmácia. Laboratory for Molecular Modeling and Drug Design. Goiânia, GO, Brasil.Universidade Federal de Goiás. Faculdade de Farmácia. Laboratory for Molecular Modeling and Drug Design. Goiânia, GO, Brasil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.State University of Campinas. Biology Institute. Laboratory of Leishmania Biology Infection Studies. Department of Animal Biology. Campinas, SP, Brasil.State University of Campinas. Biology Institute. Laboratory of Leishmania Biology Infection Studies. Department of Animal Biology. Campinas, SP, Brasil.University of North Carolina. Eshelman School of Pharmacy. Laboratory for Molecular Modeling. Division of Chemical Biology and Medicinal Chemistry. Chapel Hill, NC, USA / Odessa National Polytechnic University. Department of Chemical Technology. Odessa, Ukraine.London School of Hygiene and Tropical Medicine. Department of Pathogen Molecular Biology. London, UK.Universidade Federal de Goiás. Faculdade de Farmácia. Laboratory for Molecular Modeling and Drug Design. Goiânia, GO, Brasil.Leishmaniasis is a neglected tropical disease caused by parasites of the genus Leishmania (NTD) endemic in 98 countries. Although some drugs are available, current treatments deal with issues such as toxicity, low efficacy, and emergence of resistance. Therefore, there is an urgent need to identify new targets for the development of new antileishmanial drugs. Protein kinases (PKs), which play an essential role in many biological processes, have become potential drug targets for many parasitic diseases. A refined bioinformatics pipeline was applied in order to define and compare the kinomes of L. infantum and L. braziliensis, species that cause cutaneous and visceral manifestations of leishmaniasis in the Americas, the latter being potentially fatal if untreated. Respectively, 224 and 221 PKs were identified in L. infantum and L. braziliensis overall. Almost all unclassified eukaryotic PKs were assigned to six of nine major kinase groups and, consequently, most have been classified into family and subfamily. Furthermore, revealing the kinomes for both Leishmania species allowed for the prioritization of potential drug targets that could be explored for discovering new drugs against leishmaniasis. Finally, we used a drug repurposing approach and prioritized seven approved drugs and investigational compounds to be experimentally tested against Leishmania. Trametinib and NMS-1286937 inhibited the growth of L. infantum and L. braziliensis promastigotes and amastigotes and therefore might be good candidates for the drug repurposing pipeline

Water-soluble glutamic acid derivatives produced in culture by Penicillium solitum IS1-A from King George Island, Maritime Antarctica

A new method of screening was developed to generate 770 organic and water-soluble fractions from extracts of nine species of marine sponges, from the growth media of 18 species of marine-derived fungi, and from the growth media of 13 species of endophytic fungi. The screening results indicated that water-soluble fractions displayed significant bioactivity in cytotoxic, antibiotic, anti-Leishmania, anti-Trypanosoma cruzi, and inhibition of proteasome assays. Purification of water-soluble fractions from the growth medium of Penicillium solitum IS1-A provided the new glutamic acid derivatives solitumine A (1), solitumine B (2), and solitumidines A-D (3-6). The structures of compounds 1-6 have been established by analysis of spectroscopic data, chemical derivatizations, and vibrational circular dichroism calculations. Although no biological activity could be observed for compounds 1-6, the new structures reported for 1-6 indicate that the investigation of water-soluble natural products represents a relevant strategy in finding new secondary metabolites8315565COORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPsem informação2013/50228-8; 2014/ 25222-9; 2016/21341-9; 2017/06014-4; 2013/23153-7; 2016/16033-