Agbale Caleb Mawuli, Cardoso Marlon Henrique, Galyuon Isaac Kojo, Franco Octávio Luiz
School of Biological Sciences, College of Agriculture and Natural Sciences, University of Cape Coast, Cape Coast, Ghana and S-Inova Biotech, Programa de Pós-Graduação em Biotecnologia, Universidade Católica Dom Bosco, 79117-900 Campo Grande, MS, Brazil.
S-Inova Biotech, Programa de Pós-Graduação em Biotecnologia, Universidade Católica Dom Bosco, 79117-900 Campo Grande, MS, Brazil.
Metallomics. 2016 Nov 9;8(11):1159-1169. doi: 10.1039/c6mt00133e.
The accidental discovery of cisplatin some 50 years ago generated renewed interest in metallopharmaceuticals. Beyond cisplatin, many useful metallodrugs have been synthesized for the diagnosis and treatment of various diseases, but toxicity concerns, and the propensity to induce chemoresistance and secondary cancers make it imperative to search for novel metallodrugs that address these limitations. The Amino Terminal Cu(ii) and Ni(ii) (ATCUN) binding motif has emerged as a suitable template to design catalytic metallodrugs with nuclease and protease activities. Unlike their classical counterparts, ATCUN-based metallodrugs exhibit low toxicity, employ novel mechanisms to irreversibly inactivate disease-associated genes or proteins providing in principle, a channel to circumvent the rapid emergence of chemoresistance. The ATCUN motif thus presents novel strategies for the treatment of many diseases including cancers, HIV and infections caused by drug-resistant bacteria at the genetic level. This review discusses their design, mechanisms of action and potential for further development to expand their scope of application.
大约50年前顺铂的意外发现重新激发了人们对金属药物的兴趣。除了顺铂之外，许多有用的金属药物已被合成用于各种疾病的诊断和治疗，但毒性问题以及诱导化疗耐药性和继发性癌症的倾向使得寻找解决这些局限性的新型金属药物势在必行。氨基末端铜（II）和镍（II）（ATCUN）结合基序已成为设计具有核酸酶和蛋白酶活性的催化金属药物的合适模板。与传统的金属药物不同，基于ATCUN的金属药物毒性低，采用新机制不可逆地使与疾病相关的基因或蛋白质失活，原则上提供了一条规避化疗耐药性快速出现的途径。因此，ATCUN基序为在基因水平上治疗包括癌症、艾滋病毒和耐药细菌引起的感染在内的许多疾病提供了新策略。本综述讨论了它们的设计、作用机制以及进一步开发以扩大其应用范围的潜力。
