Heat Shock Proteins Revisited: Using a Mutasynthetically Generated Reblastatin Library to Compare the Inhibition of Human and Leishmania Hsp90s

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Mohammadi-Ostad-Kalayeh, Sona ^{[1, 2]} ; Stahl, Frank ^{[3, 4]} ; Scheper, Thomas ^{[3, 4]} ; Kock, Klaus ^[5] ; Herrmann, Christian ^[5] ; Batista, Fernanda Aparecida Heleno ^[6] ; Borges, Julio Cesar ^[6] ; Sasse, Florenz ^[7] ; Eichner, Simone ^{[8, 9]} ; Ongouta, Jekaterina ^{[8, 9]} ; Zeilinger, Carsten ^{[1, 2]} ; Kirschning, Andreas ^{[8, 9]}

Afiliação do(s) autor(es)

^[1] Leibniz Univ Hannover, Inst Biophys, Schneiderberg 38, D-30167 Hannover - Germany

^[2] Leibniz Univ Hannover, Ctr Biomol Drug Res BMWZ, Schneiderberg 38, D-30167 Hannover - Germany

^[3] Leibniz Univ Hannover, Inst Tech Chem, Callinstr 5, D-30167 Hannover - Germany

^[4] Leibniz Univ Hannover, Ctr Biomol Drug Res BMWZ, Callinstr 5, D-30167 Hannover - Germany

^[5] Ruhr Univ Bochum, Phys Chem 1, Univ Str 150, D-44801 Bochum - Germany

^[6] Univ Sao Paulo, Sao Carlos Inst Chem, BR-13560970 Sao Carlos, SP - Brazil

^[7] Helmholtz Ctr Infect Res HZI, Dept Biol Chem, Inhoffenstr 7, D-38124 Braunschweig - Germany

^[8] Leibniz Univ Hannover, Inst Organ Chem, Schneiderberg 1B, D-30167 Hannover - Germany

^[9] Leibniz Univ Hannover, Ctr Biomol Drug Res BMWZ, Schneiderberg 1B, D-30167 Hannover - Germany

• Tipo de documento: Artigo Científico
• Fonte: CHEMBIOCHEM; v. 19, n. 6, p. 562-574, MAR 16 2018.
• Citações Web of Science: 3

Resumo

Thirteen new reblastatin derivatives, with alkynyl, amino and fluoro substituents on the aromatic ring, were prepared by a chemo-biosynthetic approach using an AHBA(-) mutant strain of Streptomyces hygroscopicus, the geldanamycin producer. The inhibitory potencies of these mutaproducts and of an extended library of natural products and derivatives were probed with purified heat shock proteins (Hsps), obtained from Leishmania braziliensis (LbHsp90) as well as from human sources (HsHsp90). We determined the activities of potential inhibitors by means of a displacement assay in which fluorescence-labelled ATP competes for the ATP binding sites of Hsps in the presence of the inhibitor in question. The results were compared with those of cell-based assays and, in selected cases, of isothermal titration calorimetry (ITC) measurements. In essence, reblastatin derivatives are also able to bind effectively to the ATP-binding site of LbHsp90, and for selected derivatives, moderate differences in binding to LbHsp90 and HsHsp90 were encountered. This work demonstrates that parasitic heat shock proteins can be developed as potential pharmaceutical targets. (AU)

• Processo FAPESP: 14/07206-6 - Estudos da HSP70 mitocondrial de humanos e de protozoários: abordagem estrutural e funcional
• Beneficiário: Julio Cesar Borges
• Linha de fomento: Auxílio à Pesquisa - Regular
• Processo FAPESP: 12/50161-8 - Estudo da estrutura e função da chaperona Hsp90 com ênfase no seu papel em homeostase celular
• Beneficiário: Carlos Henrique Inacio Ramos
• Linha de fomento: Auxílio à Pesquisa - Temático