Metallodrugs are unique: opportunities and challenges of discovery and development

Elizabeth J Anthony, Elizabeth M Bolitho, Hannah E Bridgewater, Oliver W L Carter, Jane M Donnelly, Cinzia Imberti, Edward C Lant, Frederik Lermyte, Russell J Needham, Marta Palau, Peter J Sadler, Huayun Shi, Fang-Xin Wang, Wen-Ying Zhang, Zijin Zhang

Research output: Contribution to journalArticlepeer-review

331 Citations (Scopus)
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Abstract

Metals play vital roles in nutrients and medicines and provide chemical functionalities that are not accessible to purely organic compounds. At least 10 metals are essential for human life and about 46 other non-essential metals (including radionuclides) are also used in drug therapies and diagnostic agents. These include platinum drugs (in 50% of cancer chemotherapies), lithium (bipolar disorders), silver (antimicrobials), and bismuth (broad-spectrum antibiotics). While the quest for novel and better drugs is now as urgent as ever, drug discovery and development pipelines established for organic drugs and based on target identification and high-throughput screening of compound libraries are less effective when applied to metallodrugs. Metallodrugs are often prodrugs which undergo activation by ligand substitution or redox reactions, and are multi-targeting, all of which need to be considered when establishing structure-activity relationships. We focus on early-stage in vitro drug discovery, highlighting the challenges of evaluating anticancer, antimicrobial and antiviral metallo-pharmacophores in cultured cells, and identifying their targets. We highlight advances in the application of metal-specific techniques that can assist the preclinical development, including synchrotron X-ray spectro(micro)scopy, luminescence, and mass spectrometry-based methods, combined with proteomic and genomic (metallomic) approaches. A deeper understanding of the behavior of metals and metallodrugs in biological systems is not only key to the design of novel agents with unique mechanisms of action, but also to new understanding of clinically-established drugs.

Original languageEnglish
Pages (from-to)12888-12917
Number of pages30
JournalChemical Science
Volume11
Issue number48
Early online date12 Nov 2020
DOIs
Publication statusPublished - 28 Dec 2020
Externally publishedYes

Bibliographical note

Open Access, licensed under a Creative Commons Attribution 3.0 Unported license (CC-BY)

Funder


Funding Information: We thank the Biotechnology and Biological Sciences Research Council, BBSRC (EJA), the Warwick Collaborative Postgraduate Research Scholarship (EMB), Engineering Physical Sciences Research Council EPSRC (studentships for EMB, HEB, OWLC, ECL, and grants EP/N033191/1 and EP/P030572/1), Diamond Light Source (EMB), the Global Challenges Research Fund (HEB) the US-UK Fulbright Commission (JMD), the Wellcome Trust (209173/Z/17/Z, CI), the LOEWE project TRABITA funded by the Ministry of Higher Education, Research and the Arts (HMWK) of the state of Hesse (FL) the Warwick EU Chancellor's Scholarship (MP) Warwick Chancellor's Scholarship (WZ) and the Chinese Scholarship Council, CSC (FXW and ZZ). We also acknowledge support from Anglo American Platinum (RJN, HS), Bruker (ECL) and GoldenKeys High-tech Materials Co., Ltd (OWLC).

ASJC Scopus subject areas

  • Chemistry(all)

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