Cernauskiene Inga, Navo Claudio D, Labão-Almeida Carlos, J Proctor Rupert S, Gless Bengt H, Khaw Wei Ting, Tang Cong, Muriel-Olaya M Milagros, Jiménez-Osés Gonzalo, L Bernardes Gonçalo J
Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, U.K.
Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Building 800, Derio 48160, Spain.
J Am Chem Soc. 2025 Jul 16;147(28):24691-24698. doi: 10.1021/jacs.5c05952. Epub 2025 Jul 3.
Carbon monoxide (CO) has demonstrated therapeutic benefits in reactive oxygen species (ROS)-rich environments, such as inflammation and cancer. However, the targeted delivery of CO remains challenging, limiting its clinical application and necessitating the development of improved CO-prodrugs. Herein, we report a radical-activated, metal-free, CO-prodrug designed to address delivery limitations and avoid metal-associated toxicity. This tertiary aldehyde-based prodrug is stable under physiological conditions and, upon activation by a radical trigger, releases CO, 2-ethyl-1-butene, and a nontoxic thiol carrier. The stability of the CO-prodrug building block allows for its incorporation into synthetic peptides via solid-phase peptide synthesis and site-specific bioconjugation to therapeutic antibodies. We synthesized trastuzumab conjugates with a CO-prodrug-to-antibody ratio of 23 and demonstrated efficient, tumor-specific CO release in HER2-high-expressing cells. These findings open new avenues for investigating the therapeutic effects of CO. We anticipate that our metal-free CO-prodrug strategy will be broadly applicable to a wide range of synthetic peptide- and protein-based therapeutics.
一氧化碳（CO）已在富含活性氧（ROS）的环境中，如炎症和癌症中，展现出治疗益处。然而，CO的靶向递送仍然具有挑战性，限制了其临床应用，因此需要开发改进的CO前药。在此，我们报告了一种自由基激活、无金属的CO前药，旨在解决递送限制并避免与金属相关的毒性。这种基于叔醛的前药在生理条件下稳定，在自由基触发激活后，释放出CO、2-乙基-1-丁烯和一种无毒的硫醇载体。CO前药构建块的稳定性使其能够通过固相肽合成并入合成肽，并与治疗性抗体进行位点特异性生物共轭。我们合成了CO前药与抗体比例为23的曲妥珠单抗缀合物，并在HER2高表达细胞中证明了高效且肿瘤特异性的CO释放。这些发现为研究CO的治疗效果开辟了新途径。我们预计，我们的无金属CO前药策略将广泛适用于各种基于合成肽和蛋白质的治疗方法。
