Selective targeting of zinc finger domains with metallodrugs for therapy of parasitic diseases

• Grant number: 18/21120-8
• Support type: Regular Research Grants
• Duration: June 01, 2019 - May 31, 2021
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Inorganic Chemistry
• Cooperation agreement: Cardiff University
• Mobility Program: SPRINT - Projetos de pesquisa - Mobilidade
• Principal Investigator: Camilla Abbehausen
• Grantee: Camilla Abbehausen
• Principal investigator abroad: Angela Casini
• Institution abroad: Cardiff University, Wales
• Home Institution: Instituto de Química (IQ). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 17/12719-0 - Fighting bacterial resistance: metal complexes and the metallo-beta-lactamases inhibition, AP.R

Abstract

In this project, several metal-based compounds will be systematically developed and evaluated to selectively target zinc finger domains (ZF). Based on the recent report that organometallic gold(III) cyclometalated compounds can selectively target PARP-1 ZF domains in a combination of Cys3His (PARP-1) with Cys2His2 (commonly found in transcription factor), we propose to rationalize the selectivity of metal-based compounds to develop novel drugs to target parasitic, specially Leishmania zinc finger domains. Also, X-ray absorption (XAS) studies have revealed the influences of the ligand and ZF type on the metal substitution reaction involved, elucidating mechanisms of the interaction of Au(I) and Au(III) compounds with NCp7 and with Sp1 ZF domains. This proposal supports a joint effort of the proponents to combine their expertise in the direction of developing selective anti-leishmaniasis drugs targeting zinc finger domains, offering less toxic drugs for these therapies. The work plan is summarized in some steps: (i) screen the compounds according to the anti-leishmaniasis activity in vitro (ii) evaluating the selectivity of Pt(II), Pd(II), Au(III), Au(I), Co(II) and Co(III) compounds by HPLC/MS in combination of viral/parasitic and human models; (iii) designing the modification to improve selectivity where needed; (iv) study the interaction by measuring the XAS spectra of the forming adducts. (AU)