Journal
CHEMICAL SCIENCE
Volume 11, Issue 48, Pages -Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/d0sc04082g
Keywords
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Categories
Funding
- Biotechnology and Biological Sciences Research Council, BBSRC
- Warwick Collaborative Postgraduate Research Scholarship
- Engineering Physical Sciences Research Council EPSRC [EP/N033191/1, EP/P030572/1]
- Diamond Light Source
- Global Challenges Research Fund
- US-UK Fulbright Commission
- Wellcome Trust [209173/Z/17/Z]
- Ministry of Higher Education, Research and the Arts (HMWK) of the state of Hesse
- Warwick EU Chancellor's Scholarship
- Warwick Chancellor's Scholarship
- Chinese Scholarship Council, CSC
- Anglo American Platinum
- Bruker
- GoldenKeys High-tech Materials Co., Ltd
- EPSRC [EP/N033191/1, EP/P030572/1, EP/N033140/1] Funding Source: UKRI
- Wellcome Trust [209173/Z/17/Z] Funding Source: Wellcome Trust
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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.
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