Targeted metallodrug design for antileishmaniasis

• Grant number: 19/16904-2
• Support Opportunities: Regular Research Grants
• Start date: December 01, 2019
• End date: December 31, 2022
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Inorganic Chemistry
• Principal Investigator: Camilla Abbehausen
• Grantee: Camilla Abbehausen
• Host Institution: Instituto de Química (IQ). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

Leishmania protozoan parasites cause leishmaniasis, a disease with a wide range of clinical manifestations in humans, transmitted by sandfly bites. According to the World Health Organization, it is endemic in 88 countries and affects 12 million people worldwide, being one of the most neglected tropical diseases. The control of leishmaniasis is puzzling, particularly in Brazil, where it has been spreading across the country over the past 30 years, leading to an increase in the number of cases in urbanized areas. Drug options to treat patients are very limited, with antimonials having remained as the first line of treatment for all forms of leishmaniasis for almost a century, even though they are extremely toxic and require painful parenteral administration. Consequently, a major area in leishmaniasis research is the identification of less toxic new therapeutic schemes. In this context, our strategy proposes the use of novel metallodrugs - based transition metal ions, including Cu(I), Cu(II), Fe(II), Au(I), Au(III), Pd(II), Pt(II) - against different Leishmania species. Thus, validation of our mechanistic hypotheses will be achieved via an integrated investigational approach, combining chemistry, biophysics, biology, and parasitology. Furthermore, in proof-of-concept studies in vitro and in vivo, we will identify metallodrugs targeted to specific parasite components, especially zinc finger proteins and heme digestion. Furthermore, in proof-of-concept studies in vitro and in vivo, we will identify metallodrugs targeted to specific parasite components, with improved efficacy against intracellular parasitic stages and reduced side effects - a crucial bit of basic science critical to foster drug companies' investments. Our findings will stimulate discussion with different beneficiaries and the scientific community and will pave the way for further assessment of promising candidate drugs as new alternatives in the chemotherapy of leishmaniasis. This project will be held in an international collaboration context with Prof. Angela Casini, Cardiff University, already established with the SPRINT grant 2018/21120-8. (AU)

Scientific publications

(8)

(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)

ADALSTEINSSON, HEIDAR MAR; LIMA, FREDERICO A.; GALUPPO, CAROLINA; ABBEHAUSEN, CAMILLA. Evaluation of cobalt complexes with tripod ligands for zinc finger targeting. DALTON TRANSACTIONS, v. 49, n. 45, p. 16143-16153, DEC 7 2020. (17/12719-0, 19/16904-2)

AIRES, ROCHANNA L.; SANTOS, IGOR A.; FONTES, JOSIELLE, V; BERGAMINI, FERNANDO R. G.; JARDIM, ANA CAROLINA G.; ABBEHAUSEN, CAMILLA. Triphenylphosphine gold(I) derivatives promote antiviral effects against the Chikungunya virus. METALLOMICS, v. 14, n. 8, p. 12-pg., 2022-08-10. (19/16904-2)

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)

GALUPPO, CAROLINA; JUNIOR, ARNALDO GOMES DE OLIVEIRA; OLIVEIRA, LAIANE DOS SANTOS; GUARDA, PEDRO HENRIQUE DE SOUZA; BUFFON, REGINA; ABBEHAUSEN, CAMILLA. Reactivity of NiII, PdII and PtII complexes bearing phosphine ligands towards ZnII displacement and hydrolysis in Cis2His2 and Cis3His zinc-fingers domains. Journal of Inorganic Biochemistry, v. 240, p. 10-pg., 2023-01-25. (19/16904-2)

FONTES, JOSIELLE, V; SANTOS, IGOR A.; ROSA, LETICIA B.; LIMA, ROCHANNA L. A.; JARDIM, ANA C. G.; MIGUEL, DANILO C.; ABBEHAUSEN, CAMILLA. Antileishmanial and Anti-Chikungunya Activity of Cu(I)-N-Heterocyclic Carbenes. CHEMISTRYSELECT, v. 7, n. 31, p. 10-pg., 2022-08-19. (19/16904-2, 14/21129-4)

TELES, CATHERINE M.; ANTUNES, VICTOR U.; CARDOSO, RAQUEL S.; CANDIDO, TUANY Z.; LIMA, CARMEN S. P.; RUIZ, ANA LUCIA T. G.; JULIANO, MARIA A.; FAVARO, DENIZE C.; ABBEHAUSEN, CAMILLA. Functionalization of new anticancer Pt(II) complex with transferrin receptor binding peptide. Inorganica Chimica Acta, v. 511, OCT 1 2020. (19/16904-2, 16/07729-4, 12/50191-4)