Engineering a highly selective, hemoprotein-based scavenger as a carbon monoxide poisoning antidote with no hypertensive effect

• 成果类型: Article
• 署名作者: Dent, Matthew R.; DeMartino, Anthony W.; Xu, Qinzi; Chen, Xiukai; Gandhi, Alay; Hwang, Hyon S.; Bocian, Kaitlin A.; Correnti, Jacob E.; Abdelghany, Youmna; Alipour, Elmira; Ucer, K. Burak; Baker, Stephen R.; Kandada, Ajay Ram Srimath; Bulbul, Angka; Kim-Shapiro, Daniel B.; Rose, Jason J.; Tejero, Jesus; Gladwin, Mark T.
• 署名单位: Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; University System of Maryland; University of Maryland Baltimore; Wake Forest University; Wake Forest University; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14023
• DOI: 10.1073/pnas.2501389122
• 发表日期: 2025-08-12
• 关键词: cytochrome-c-oxidase; long-term mortality; nitric-oxide; transcriptional regulator; ligand-binding; human neuroglobin; heme domain; hemoglobin; DYNAMICS; protein

摘要

Carbon monoxide (CO) poisoning causes 50,000 to 100,000 emergency department visits and similar to 1,500 deaths in the United States annually. Current treatments are limited to supplemental and/or hyperbaric oxygen to accelerate CO elimination. Even with oxygen therapy, nearly half of CO poisoning survivors suffer long-term cardiac and neurocognitive deficits related to slow CO clearance, highlighting a need for point of care antidotal therapies. Given the natural interaction between CO and ferrous heme, we hypothesized that the hemoprotein RcoM, a transcriptional regulator of microbial CO metabolism, would make an ideal platform for CO-selective scavenging from endogenous hemoproteins. We engineered an RcoM truncate (RcoM-HBD-CCC) that exhibits high CO affinity (K-a,K-CO = 2.8 x 10(10) M-1), remarkable selectivity for CO over oxygen (K-a,K-O2 = 1.4 x 10(5) M-1; K-a,K-CO/K-a,K-O2 = 1.9 x 10(5)), thermal stability (T-m = 72 degrees C), and slow autoxidation rate (k(ox) = 1.1 h(-1)). In a murine model of acute CO poisoning, infused RcoM-HBD-CCC accelerated CO clearance from hemoglobin in red blood cells (RBCs) and was rapidly excreted in urine. Moreover, infused RcoM-HBD-CCC elicited minimal hypertension in mice compared to infused globins (hemoglobin, myoglobin, and neuroglobin), attributed to a comparatively limited reactivity toward nitric oxide (NO) via dioxygenation [k(NOD)(RcoM) = 6 to 8 x 10(6) M(-1)s(-1) vs k(NOD)(Hb) = 6 to 8 x 10(7) M(-1)s(-1)]. These data suggest that RcoM-HBD-CCC is a safe, selective, and efficacious CO scavenger. By limiting hypertension through minimal NO scavenging, RcoM-HBD-CCC improves end-organ adverse effects compared with other hemoprotein-based therapeutics.