Torin 2 Derivative, NCATS-SM3710, Has Potent Multistage Antimalarial Activity through Inhibition of P. falciparum Phosphatidylinositol 4-Kinase (Pf PI4KIII ss)

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Krishnan, Karthik ^[1] ; Ziniel, Peter ^[1] ; Li, Hao ^[2] ; Huang, Xiuli ^[2] ; Hupalo, Daniel ^[3] ; Gombakomba, Nita ^[1] ; Guerrero, Sandra Mendoza ^[1] ; Dotrang, Thoai ^[1] ; Lu, Xiao ^[2] ; Caridha, Diana ^[4] ; Sternberg, Anna R. ^{[5, 6, 7]} ; Hughes, Emma ^[2] ; Sun, Wei ^[2] ; Bargieri, Daniel Y. ^[8] ; Roepe, Paul D. ^{[5, 6, 7]} ; Sciotti, Richard J. ^[4] ; Wilkerson, Matthew D. ^[3] ; Dalgard, Clifton L. ^{[9, 10]} ; Tawa, Gregory J. ^[2] ; Wang, Amy Q. ^[2] ; Xu, Xin ^[2] ; Zheng, Wei ^[2] ; Sanderson, Philip E. ^[2] ; Huang, Wenwei ^[2] ; Williamson, Kim C. ^[1]

Afiliação do(s) autor(es)

^[1] Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, Bethesda, MD 20814 - USA

^[2] NIH, Natl Ctr Adv Translat Sci, Rockville, MD 20892 - USA

^[3] Uniformed Serv Univ Hlth Sci, Dept Anat Physiol & Genet, Collaborat Hlth Initiat Res Program, Bethesda, MD 20814 - USA

^[4] Walter Reed Army Inst Res, Silver Spring, MD 20910 - USA

^[5] Georgetown Univ, Dept Chem, Washington, DC 20057 - USA

^[6] Georgetown Univ, Dept Biochem, Washington, DC 20057 - USA

^[7] Georgetown Univ, Dept Cellular & Mol Biol, Washington, DC 20057 - USA

^[8] Univ Sao Paulo, Inst Biomed Sci, BR-05508 Sao Paulo - Brazil

^[9] Uniformed Serv Univ Hlth Sci, Dept Anat Physiol & Genet, Bethesda, MD 20814 - USA

^[10] Uniformed Serv Univ Hlth Sci, Amer Genome Ctr, Bethesda, MD 20814 - USA

• Tipo de documento: Artigo Científico
• Fonte: ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE; v. 3, n. 5, p. 948-964, OCT 9 2020.
• Citações Web of Science: 1

Resumo

Drug resistance is a constant threat to malaria control efforts making it important to maintain a good pipeline of new drug candidates. Of particular need are compounds that also block transmission by targeting sexual stage parasites. Mature sexual stages are relatively resistant to all currently used antimalarials except the 8-aminoquinolines that are not commonly used due to potential side effects. Here, we synthesized a new Torin 2 derivative, NCATS-SM3710 with increased aqueous solubility and specificity for Plasmodium and demonstrate potent in vivo activity against all P. berghei life cycle stages. NCATS-SM3710 also has low nanomolar EC(50)s against in vitro cultured asexual P. falciparum parasites (0.38 +/- 0.04 nM) and late stage gametocytes (5.77 +/- 1 nM). Two independent NCATS-SM3710/Torin 2 resistant P. falciparum parasite lines produced by growth in sublethal Torin 2 concentrations both had genetic changes in PF3D7\_0509800, annotated as a phosphatidylinositol 4 kinase (Pf PI4KIII ss). One line had a point mutation in the putative active site (V1357G), and the other line had a duplication of a locus containing Pf PI4KIII ss. Both lines were also resistant to other Pf PI4K inhibitors. In addition NCATS-SM3710 inhibited purified Pf PI4KIII ss with an IC50 of 2.0 +/- 0.30 nM. Together the results demonstrate that Pf PI4KIII ss is the target of Torin 2 and NCATS-SM3710 and provide new options for potent multistage drug development. (AU)

• Processo FAPESP: 13/13119-6 - Biologia celular e genética molecular de hemoparasitas
• Beneficiário: Daniel Youssef Bargieri
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores