Department of Chemistry and the Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia 30303, United States.
J Med Chem. 2024 Jun 27;67(12):9789-9815. doi: 10.1021/acs.jmedchem.4c00823. Epub 2024 Jun 12.
Carbon monoxide (CO) is endogenously produced in mammals, with blood concentrations in the high micromolar range in the hemoglobin-bound form. Further, CO has shown therapeutic effects in various animal models. Despite its reputation as a poisonous gas at high concentrations, we show that CO should have a wide enough safety margin for therapeutic applications. The analysis considers a large number of factors including levels of endogenous CO, its safety margin in comparison to commonly encountered biomolecules or drugs, anticipated enhanced safety profiles when delivered via a noninhalation mode, and the large amount of safety data from human clinical trials. It should be emphasized that having a wide enough safety margin for therapeutic use does not mean that it is benign or safe to the general public, even at low doses. We defer the latter to public health experts. Importantly, this Perspective is written for drug discovery professionals and not the general public.
一氧化碳（CO）在哺乳动物中内源性产生，血红蛋白结合形式的血液浓度处于高微摩尔范围内。此外，CO 在各种动物模型中表现出治疗效果。尽管在高浓度下 CO 被认为是一种有毒气体，但我们表明 CO 应该具有足够宽的安全范围，适用于治疗应用。该分析考虑了许多因素，包括内源性 CO 的水平、与常见生物分子或药物相比的安全裕度、通过非吸入方式给药时预期的增强的安全性特征，以及来自人类临床试验的大量安全性数据。应该强调的是，对于治疗用途有足够宽的安全裕度并不意味着它对公众（即使是低剂量）是良性或安全的。我们将后者留给公共卫生专家。重要的是，本观点是为药物发现专业人员而不是普通公众撰写的。
