GlaxoSmithKline U.K., Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G11XL, U.K.
Bioconjug Chem. 2021 Feb 17;32(2):279-289. doi: 10.1021/acs.bioconjchem.0c00662. Epub 2021 Feb 1.
Reducing the required frequence of drug dosing can improve the adherence of patients to chronic treatments. Hence, drugs with longer half-lives are highly desirable. One of the most promising approaches to extend the half-life of drugs is conjugation to human serum albumin (HSA). In this work, we describe the use of , a small-molecule noncovalent HSA binder, to extend the half-life and pharmacology of small-molecule BMP1/TLL inhibitors in humanized mice (HSA KI/KI). A series of conjugates of with BMP1/TLL inhibitors were prepared. In particular, showed good solubility and a half-life extension of >20-fold versus the parent molecule in the HSA KI/KI mice, reaching half-lives of >48 h with maintained maximal inhibition of plasma BMP1/TLL. The same conjugate showed a half-life of only 3 h in the wild-type mice, suggesting that the half-life extension was principally due to specific interactions with HSA. It is envisioned that conjugation to should be applicable to a wide range of small molecule or peptide drugs with short half-lives. In this context, AlbuBinders represent a viable alternative to existing half-life extension technologies.
降低药物给药频率可以提高患者对慢性治疗的依从性。因此，半衰期较长的药物是非常需要的。延长药物半衰期的最有前途的方法之一是与人血清白蛋白（HSA）结合。在这项工作中，我们描述了使用小分子非共价 HSA 结合物 来延长小分子 BMP1/TLL 抑制剂在人源化小鼠（HSA KI/KI）中的半衰期和药理学特性。制备了一系列与 BMP1/TLL 抑制剂的缀合物。特别是，与母体分子相比，在 HSA KI/KI 小鼠中显示出良好的溶解度和超过 20 倍的半衰期延长，半衰期超过 48 小时，同时保持对血浆 BMP1/TLL 的最大抑制作用。相同的缀合物在野生型小鼠中的半衰期仅为 3 小时，这表明半衰期的延长主要是由于与 HSA 的特异性相互作用。可以预见，与 结合应该适用于具有短半衰期的广泛的小分子或肽类药物。在这种情况下，AlbuBinders 是现有半衰期延长技术的可行替代品。
