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

• Grant number: 18/21120-8
• Support Opportunities: Regular Research Grants
• Start date: June 01, 2019
• End date: May 31, 2021
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Inorganic Chemistry
• Agreement: Cardiff University
• Mobility Program: SPRINT - Projetos de pesquisa - Mobilidade
• Principal Investigator: Camilla Abbehausen
• Grantee: Camilla Abbehausen
• Principal researcher abroad: Angela Casini
• Institution abroad: Cardiff University, Wales
• Host 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)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

ROSA, LETICIA B.; AIRES, ROCHANNA L.; OLIVEIRA, LAIANE S.; FONTES, JOSIELLE V.; MIGUEL, DANILO C.; ABBEHAUSEN, CAMILLA. A ``Golden Age{''} for the discovery of new antileishmanial agents: Current status of leishmanicidal gold complexes and prospective targets beyond the trypanothione system. CHEMMEDCHEM, v. 16, n. 11, MAR 2021. (19/16904-2, 18/21120-8, 14/21129-4)

ROSA, LETICIA B.; AIRES, ROCHANNA L.; OLIVEIRA, LAIANE S.; FONTES, JOSIELLE V.; MIGUEL, DANILO C.; ABBEHAUSEN, CAMILLA. A "Golden Age" for the discovery of new antileishmanial agents: Current status of leishmanicidal gold complexes and prospective targets beyond the trypanothione system. CHEMMEDCHEM, v. 16, n. 11, p. 15-pg., 2021-03-22. (14/21129-4, 19/16904-2, 18/21120-8)

ROSA, LETICIA B.; GALUPPO, CAROLINA; LIMA, ROCHANNA L. A.; FONTES, JOSIELLE, V; SIQUEIRA, FABIO S.; JUDICE, WAGNER A. S.; ABBEHAUSEN, CAMILLA; MIGUEL, DANILO C.. Antileishmanial activity and insights into the mechanisms of action of symmetric Au(I) benzyl and aryl-N-heterocyclic carbenes. Journal of Inorganic Biochemistry, v. 229, p. 9-pg., 2022-04-01. (14/02205-1, 19/01678-7, 16/25112-4, 18/21120-8, 19/16904-2, 14/21129-4)