Design of novel metallodrugs and innovative administration routes for Leishmaniasis treatment

• Grant number: 22/02618-0
• Support Opportunities: Research Grants - Initial Project
• Start date: February 01, 2023
• End date: January 31, 2028
• 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
• Associated researchers: Danilo Ciccone Miguel
• Associated scholarship(s): 24/18677-1 - Metal Complex Bioconjugation as a Platform for Developing Targeted Therapies for Leishmaniasis, BP.DD; 24/09174-6 - Gold conjugates and biomolecules for the treatment of cutaneous Leishmaniasis, BP.MS; 23/12657-6 - Computational analysis of [Au(L)X] complexes as targeted Leishmania metallodrugs, BP.DD; 23/06493-0 - Cell culture routine implementation, BP.TT

Abstract

Leishmania parasites cause leishmaniasis, an endemic neglected tropical disease with several clinical manifestations in humans, including visceral (VL) and cutaneous (CL) forms. In Brazil, it has been spreading, leading to an increase in cases in urbanized areas. As a drawback, drug options are limited. For almost a century, antimonials have remained the first line of treatment, even though they are toxic and require painful parenteral administration. Consequently, a central area in leishmaniasis research is the identification of less toxic therapies. Still, most reports focus on VL, and few efforts are found on CL topical treatments. In the last case, topical administration is considered more advantageous, though few ineffective options are available. Our research group has been investigating systematic series of Au(I) and Cu(I)-N-heterocyclic carbenes (NHC) for leishmaniasis treatment. As a result, we have found chemotypes with a significant selective index. Accordingly, the project goal is the development of a topical therapy for CL based on Au(I) or Cu(I)-NHC complexes. Three different approaches are proposed to reach the goal. Firstly, the development of NHCs to modulate the lipophilicity and pKa of the final metal complexes, tuning their distribution to the parasite. Secondly, conjugation of biochemical groups to the metal complexes, such as short peptides or nucleotides to create a targeted therapy. Thirdly, the evaluation of polymeric membranes for the topical-sustained release of the metallodrugs. The design of molecules will be supported by in silico and mechanistic studies, including cell uptake, membrane permeabilization, measurements of reactive oxygen species production, mitochondrial respiratory activity, and target inhibition using cell extracts, purified proteins, or models. The sustained release will be measured by diffusion methods, in vitro protocols, and in vivo models. (AU)

Scientific publications

(5)

(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)

CASTRO, JENNYFER; CLAUSS, GUSTAVO; FONTES, JOSIELLE V.; OLIVEIRA, LAIANE S.; ABBEHAUSEN, CAMILLA. Oxidative Stress Mechanism by Gold Compounds: A Close Look at Total ROS Increase and the Inhibition of Antioxidant Enzymes. CHEMISTRY-AN ASIAN JOURNAL, v. N/A, p. 14-pg., 2024-11-16. (22/02618-0, 23/12657-6, 22/06410-5)

OLIVEIRA, LAIANE S.; ROSA, LETICIA B.; AFFONSO, DANIELE D.; SANTOS, IGOR A.; DA SILVA, JENNYFER C.; RODRIGUES, GUSTAVO C.; HARRIS, MARK; JARDIM, ANA CAROLINA G.; NAKAHATA, DOUGLAS H.; SABINO, JOSE R.; et al. Novel bidentate amine ligand and the interplay between Pd(II) and Pt(II) coordination and biological activity. CHEMBIOCHEM, v. 25, n. 6, p. 11-pg., 2024-02-12. (22/02618-0, 19/16904-2, 23/06493-0)

MINORI, KAREN; GADELHA, FERNANDA R.; BONSIGNORE, RICCARDO; ALCANTAR, GUILLERMO MORENO; FONTES, JOSIELLE, V; ABBEHAUSEN, CAMILLA; BRIOSCHI, MARIANA B. C.; DE SOUSA, LIZANDRA MAIA; CONSONNI, SILVIO R.; CASINI, ANGELA; et al. An organogold compound impairs Leishmania amazonensis amastigotes survival and delays lesion progression in murine cutaneous leishmaniasis: Mechanistic insights. Biochemical Pharmacology, v. 232, p. 9-pg., 2024-12-16. (21/01504-9, 22/06410-5, 22/02618-0, 14/21129-4)

OLIVEIRA, IGOR S.; GARCIA, MARCUS S. A.; CASSANI, NATASHA M.; OLIVEIRA, ANA L. C.; FREITAS, LARA C. F.; BERTOLINI, VITOR K. S.; CASTRO, JENNYFER; CLAUSS, GUSTAVO; HONORATO, JOAO; GADELHA, FERNANDA R.; et al. Exploring antiviral and antiparasitic activity of gold N-heterocyclic carbenes with thiolate ligands. DALTON TRANSACTIONS, v. 53, n. 47, p. 11-pg., 2024-08-15. (22/02618-0, 23/06493-0, 23/12657-6)

RODRIGUES, GUSTAVO C.; BARRIONUEVO, MANOEL V. F.; SAN-MIGUEL, MIGUEL A.; ABBEHAUSEN, CAMILLA. Unraveling ligand exchange reactions in linear neutral Au(i) and Cu(i) N-heterocyclic carbene complexes for biological applications. NEW JOURNAL OF CHEMISTRY, v. 48, n. 5, p. 8-pg., 2023-12-27. (17/26105-4, 13/07296-2, 20/11727-2, 16/23891-6, 22/02618-0)