Zinc Fingers as Target for Metallodrugs

Published by Camilla Abbehausen

January 30, 2024

Summary

Zinc finger proteins, constituting one of the most prevalent protein families, exhibit diverse structures and functions. The structural integrity conferred by the zinc ion is pivotal for their precise recognition of DNA, RNA, and protein sequences. These versatile zinc fingers play crucial roles in transcription, protein degradation, DNA repair, cell migration, and other cellular processes. Recent studies have shed light on their extensive involvement in various diseases.

Despite the identification of numerous zinc finger variants, a comprehensive understanding of their functions is still in progress. The exploration of genomes and proteomes continues to unveil novel zinc finger attributes. As their roles in diseases become more apparent, zinc fingers have garnered attention as potential drug targets.

Inhibiting zinc finger function through the replacement of Zn(II) with alternative metal ions has emerged as a prominent method. On one hand, zinc fingers contribute to the toxicity mechanisms of Ni(II), Hg(II), Cd(II), and others. On the other hand, compounds such as gold, platinum, cobalt, and selenium complexes have been developed as zinc finger inhibitors for therapeutic purposes. Overcoming the challenge of achieving selectivity is a primary focus in the design of therapeutic zinc finger inhibitors.

Recent advancements in compound design and the elucidation of zinc substitution mechanisms have revitalized prospects for selectively inhibiting zinc fingers through metal complexes. This renewed understanding opens avenues for developing targeted therapies and refining drug design strategies for zinc finger-associated diseases. Our research group is devoted to the design of inhibitors e study of inhibition mechanisms.

Research Outcomes

(1) Galuppo, C.; Gomes de Oliveira Junior, A.; dos Santos Oliveira, L.; de Souza Guarda, P. H.; Buffon, R.; Abbehausen, C. Reactivity of NiII, PdII and PtII Complexes Bearing Phosphine Ligands towards ZnII Displacement and Hydrolysis in Cis2His2 and Cis3His Zinc-Fingers Domains. J Inorg Biochem 2023, 240, 112117. https://doi.org/10.1016/j.jinorgbio.2022.112117.

(2) Aðalsteinsson, H. M.; Lima, F. A.; Galuppo, C.; Abbehausen, C. Evaluation of Cobalt Complexes with Tripod Ligands for Zinc Finger Targeting. Dalton Trans. 2020, 49 (45), 16143–16153. https://doi.org/10.1039/D0DT00067A.

(3) Abbehausen, C. Zinc Finger Domains as Therapeutic Targets for Metal-Based Compounds – an Update. Metallomics2019, 11 (1), 15–28. https://doi.org/10.1039/C8MT00262B.

(4) de Arruda, E. G. R.; Rocha, B. A.; Barrionuevo, M. V. F.; Aðalsteinsson, H. M.; Galdino, F. E.; Loh, W.; Lima, F. A.; Abbehausen, C. The Influence of Zn ^II Coordination Sphere and Chemical Structure over the Reactivity of Metallo-β-Lactamase Model Compounds. Dalton Trans. 2019, 48 (9), 2900–2916. https://doi.org/10.1039/C8DT03905D.

(5) Abbehausen, C.; de Paiva, R. E. F.; Bjornsson, R.; Gomes, S. Q.; Du, Z.; Corbi, P. P.; Lima, F. A.; Farrell, N. X-Ray Absorption Spectroscopy Combined with Time-Dependent Density Functional Theory Elucidates Differential Substitution Pathways of Au(I) and Au(III) with Zinc Fingers. Inorg. Chem. 2018, 57 (1), 218–230. https://doi.org/10.1021/acs.inorgchem.7b02406.

(6) Abbehausen, C.; Peterson, E. J.; de Paiva, R. E. F.; Corbi, P. P.; Formiga, A. L. B.; Qu, Y.; Farrell, N. P. Gold(I)-Phosphine-N-Heterocycles: Biological Activity and Specific (Ligand) Interactions on the C-Terminal HIVNCp7 Zinc Finger. Inorg. Chem. 2013, 52 (19), 11280–11287. https://doi.org/10.1021/ic401535s.

(7) Abbehausen, C.; Manzano, C. M.; Corbi, P. P.; Farrell, N. P. Effects of Coordination Mode of 2-Mercaptothiazoline on Reactivity of Au(I) Compounds with Thiols and Sulfur-Containing Proteins. J. Inorg. Biochem. 2016, 165, 136–145. https://doi.org/10.1016/j.jinorgbio.2016.05.011.

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