Identification of potential inhibitors of casein kinase 2 alpha of Plasmodium falciparum with potent in vitro activity
| Main Author: | |
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| Publication Date: | 2023 |
| Other Authors: | , , , , , , , , , , , , , , , , |
| Format: | Article |
| Language: | eng |
| Source: | Repositórios Científicos de Acesso Aberto de Portugal (RCAAP) |
| Download full: | http://hdl.handle.net/10362/164975 |
Summary: | Funding Information: The authors are incredibly grateful to Brazilian funding agencies Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), CNPq, CAPES, Fundação de Apoio à Pesquisa do Estado de Goiás (FAPEG), and to the Swedish Research Council (grants 2016–05627 and 2021–03667). K.C.P.T. thanks FAPESP (grants 2018/05926–2, and 2019/17062–5). FAPESP funded T.A.T. (2019/27626-3), J.V.B.B. (2019/21854-4), K.B.M. and R.M.C. (2014/50897-0), V.M.A. (2022/00743-2), G.C.C. (2015/20774-6), and F.T.M.C. (grants 2017/18611–7 and 2018/07007–4). L.C.S.A. was funded by CNPq (162117/2018– 3). E.B. was supported by FAPESP (2015/03553-6 and 2018/07007–4) and CAPES (88887.304810/2018–00). J.V.B.B. and J.T.M.F. were supported by CAPES (Finance Code 001). C.H.A. and M.M. thanks FAPEG (grants 20171026700006 and 202010267000272). C.H.A. thanks the “L'Oréal-UNESCO-ABC Para Mulheres na Ciência” and “L’Oréal-UNESCO International Rising Talents” for the awards and fellowships received, which partially funded this work. C.H.A. and F.T.M.C. are CNPq research fellows. We are thankful to Liam B. King for his critical review of the report. Publisher Copyright: © 2023 American Society for Microbiology. All Rights Reserved. |
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Identification of potential inhibitors of casein kinase 2 alpha of Plasmodium falciparum with potent in vitro activityantimalarialsdockingmalariaquinazolinevirtual screeningRM Therapeutics. PharmacologyQR MicrobiologyPharmacologyPharmacology (medical)Infectious DiseasesDrug DiscoveryParasitologySDG 3 - Good Health and Well-beingFunding Information: The authors are incredibly grateful to Brazilian funding agencies Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), CNPq, CAPES, Fundação de Apoio à Pesquisa do Estado de Goiás (FAPEG), and to the Swedish Research Council (grants 2016–05627 and 2021–03667). K.C.P.T. thanks FAPESP (grants 2018/05926–2, and 2019/17062–5). FAPESP funded T.A.T. (2019/27626-3), J.V.B.B. (2019/21854-4), K.B.M. and R.M.C. (2014/50897-0), V.M.A. (2022/00743-2), G.C.C. (2015/20774-6), and F.T.M.C. (grants 2017/18611–7 and 2018/07007–4). L.C.S.A. was funded by CNPq (162117/2018– 3). E.B. was supported by FAPESP (2015/03553-6 and 2018/07007–4) and CAPES (88887.304810/2018–00). J.V.B.B. and J.T.M.F. were supported by CAPES (Finance Code 001). C.H.A. and M.M. thanks FAPEG (grants 20171026700006 and 202010267000272). C.H.A. thanks the “L'Oréal-UNESCO-ABC Para Mulheres na Ciência” and “L’Oréal-UNESCO International Rising Talents” for the awards and fellowships received, which partially funded this work. C.H.A. and F.T.M.C. are CNPq research fellows. We are thankful to Liam B. King for his critical review of the report. Publisher Copyright: © 2023 American Society for Microbiology. All Rights Reserved.Drug resistance to commercially available antimalarials is a major obstacle in malaria control and elimination, creating the need to find new antiparasitic compounds with novel mechanisms of action. The success of kinase inhibitors for oncological treatments has paved the way for the exploitation of protein kinases as drug targets in various diseases, including malaria. Casein kinases are ubiquitous serine/threonine kinases involved in a wide range of cellular processes such as mitotic checkpoint signaling, DNA damage response, and circadian rhythm. In Plasmodium, it is suggested that these protein kinases are essential for both asexual and sexual blood-stage parasites, reinforcing their potential as targets for multi-stage antimalarials. To identify new putative PfCK2α inhibitors, we utilized an in silico chemogenomic strategy involving virtual screening with docking simulations and quantitative structure-activity relationship predictions. Our investigation resulted in the discovery of a new quinazoline molecule (542), which exhibited potent activity against asexual blood stages and a high selectivity index (>100). Subsequently, we conducted chemical-genetic interaction analysis on yeasts with mutations in casein kinases. Our chemical-genetic interaction results are consistent with the hypothesis that 542 inhibits yeast Cka1, which has a hinge region with high similarity to PfCK2α. This finding is in agreement with our in silico results suggesting that 542 inhibits PfCK2α via hinge region interaction.Vector borne diseases and pathogens (VBD)Global Health and Tropical Medicine (GHTM)Instituto de Higiene e Medicina Tropical (IHMT)RUNTomaz, Kaira C.P.Tavella, Tatyana A.Borba, Joyce V.B.Salazar-Alvarez, Luis C.Levandoski, João E.Mottin, MelinaSousa, Bruna K.P.Moreira-Filho, José T.Almeida, Vitor M.Clementino, Leandro C.Bourgard, CatarinaMassirer, Katlin B.Couñago, Rafael M.Andrade, Carolina H.Sunnerhagen, PerBilsland, ElizabethCassiano, Gustavo C.Costa, Fabio T.M.2024-03-14T23:59:12Z2023-112023-11-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article15application/pdfhttp://hdl.handle.net/10362/164975eng0066-4804PURE: 83028296https://doi.org/10.1128/AAC.00589-23info:eu-repo/semantics/openAccessreponame:Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)instname:FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologiainstacron:RCAAP2024-05-22T18:19:36Zoai:run.unl.pt:10362/164975Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireinfo@rcaap.ptopendoar:https://opendoar.ac.uk/repository/71602025-05-28T17:50:27.919162Repositórios Científicos de Acesso Aberto de Portugal (RCAAP) - FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologiafalse |
| dc.title.none.fl_str_mv |
Identification of potential inhibitors of casein kinase 2 alpha of Plasmodium falciparum with potent in vitro activity |
| title |
Identification of potential inhibitors of casein kinase 2 alpha of Plasmodium falciparum with potent in vitro activity |
| spellingShingle |
Identification of potential inhibitors of casein kinase 2 alpha of Plasmodium falciparum with potent in vitro activity Tomaz, Kaira C.P. antimalarials docking malaria quinazoline virtual screening RM Therapeutics. Pharmacology QR Microbiology Pharmacology Pharmacology (medical) Infectious Diseases Drug Discovery Parasitology SDG 3 - Good Health and Well-being |
| title_short |
Identification of potential inhibitors of casein kinase 2 alpha of Plasmodium falciparum with potent in vitro activity |
| title_full |
Identification of potential inhibitors of casein kinase 2 alpha of Plasmodium falciparum with potent in vitro activity |
| title_fullStr |
Identification of potential inhibitors of casein kinase 2 alpha of Plasmodium falciparum with potent in vitro activity |
| title_full_unstemmed |
Identification of potential inhibitors of casein kinase 2 alpha of Plasmodium falciparum with potent in vitro activity |
| title_sort |
Identification of potential inhibitors of casein kinase 2 alpha of Plasmodium falciparum with potent in vitro activity |
| author |
Tomaz, Kaira C.P. |
| author_facet |
Tomaz, Kaira C.P. Tavella, Tatyana A. Borba, Joyce V.B. Salazar-Alvarez, Luis C. Levandoski, João E. Mottin, Melina Sousa, Bruna K.P. Moreira-Filho, José T. Almeida, Vitor M. Clementino, Leandro C. Bourgard, Catarina Massirer, Katlin B. Couñago, Rafael M. Andrade, Carolina H. Sunnerhagen, Per Bilsland, Elizabeth Cassiano, Gustavo C. Costa, Fabio T.M. |
| author_role |
author |
| author2 |
Tavella, Tatyana A. Borba, Joyce V.B. Salazar-Alvarez, Luis C. Levandoski, João E. Mottin, Melina Sousa, Bruna K.P. Moreira-Filho, José T. Almeida, Vitor M. Clementino, Leandro C. Bourgard, Catarina Massirer, Katlin B. Couñago, Rafael M. Andrade, Carolina H. Sunnerhagen, Per Bilsland, Elizabeth Cassiano, Gustavo C. Costa, Fabio T.M. |
| author2_role |
author author author author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Vector borne diseases and pathogens (VBD) Global Health and Tropical Medicine (GHTM) Instituto de Higiene e Medicina Tropical (IHMT) RUN |
| dc.contributor.author.fl_str_mv |
Tomaz, Kaira C.P. Tavella, Tatyana A. Borba, Joyce V.B. Salazar-Alvarez, Luis C. Levandoski, João E. Mottin, Melina Sousa, Bruna K.P. Moreira-Filho, José T. Almeida, Vitor M. Clementino, Leandro C. Bourgard, Catarina Massirer, Katlin B. Couñago, Rafael M. Andrade, Carolina H. Sunnerhagen, Per Bilsland, Elizabeth Cassiano, Gustavo C. Costa, Fabio T.M. |
| dc.subject.por.fl_str_mv |
antimalarials docking malaria quinazoline virtual screening RM Therapeutics. Pharmacology QR Microbiology Pharmacology Pharmacology (medical) Infectious Diseases Drug Discovery Parasitology SDG 3 - Good Health and Well-being |
| topic |
antimalarials docking malaria quinazoline virtual screening RM Therapeutics. Pharmacology QR Microbiology Pharmacology Pharmacology (medical) Infectious Diseases Drug Discovery Parasitology SDG 3 - Good Health and Well-being |
| description |
Funding Information: The authors are incredibly grateful to Brazilian funding agencies Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), CNPq, CAPES, Fundação de Apoio à Pesquisa do Estado de Goiás (FAPEG), and to the Swedish Research Council (grants 2016–05627 and 2021–03667). K.C.P.T. thanks FAPESP (grants 2018/05926–2, and 2019/17062–5). FAPESP funded T.A.T. (2019/27626-3), J.V.B.B. (2019/21854-4), K.B.M. and R.M.C. (2014/50897-0), V.M.A. (2022/00743-2), G.C.C. (2015/20774-6), and F.T.M.C. (grants 2017/18611–7 and 2018/07007–4). L.C.S.A. was funded by CNPq (162117/2018– 3). E.B. was supported by FAPESP (2015/03553-6 and 2018/07007–4) and CAPES (88887.304810/2018–00). J.V.B.B. and J.T.M.F. were supported by CAPES (Finance Code 001). C.H.A. and M.M. thanks FAPEG (grants 20171026700006 and 202010267000272). C.H.A. thanks the “L'Oréal-UNESCO-ABC Para Mulheres na Ciência” and “L’Oréal-UNESCO International Rising Talents” for the awards and fellowships received, which partially funded this work. C.H.A. and F.T.M.C. are CNPq research fellows. We are thankful to Liam B. King for his critical review of the report. Publisher Copyright: © 2023 American Society for Microbiology. All Rights Reserved. |
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2023 |
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2023-11 2023-11-01T00:00:00Z 2024-03-14T23:59:12Z |
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