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In Vivo Half-Life Extension of BMP1/TLL Metalloproteinase Inhibitors Using Small-Molecule Human Serum Albumin Binders
Bioconjugate Chemistry ( IF 4.7 ) Pub Date : 2021-02-01 , DOI: 10.1021/acs.bioconjchem.0c00662
Julien C Vantourout 1, 2 , Andrew M Mason 1 , Josephine Yuen 3 , Graham L Simpson 1 , Ghotas Evindar 3 , Letian Kuai 3 , Michael Hobbs 1 , Emma Edgar 1 , Saul Needle 4 , Xiaopeng Bai 3 , Steve Wilson 1 , Paul Scott-Stevens 1 , William Traylen 1 , Kim Lambert 1 , Neil Young 1 , Shenaz Bunally 1 , Scott G Summerfield 1 , Richard Snell 1 , Rakesh Lad 1 , Eric Shi 3 , Steven Skinner 3 , Lisa Shewchuk 4 , Allan J B Watson 5 , Chun-Wa Chung 1 , Sandeep Pal 1 , Dennis A Holt 4 , Lara S Kallander 4 , Joanne Prendergast 4 , Katrina Rivera 4 , David G Washburn 4 , Mark R Harpel 4 , Christopher Arico-Muendel 3 , Albert Isidro-Llobet 1
Affiliation  

Reducing the required frequence of drug dosing can improve the adherence of patients to chronic treatments. Hence, drugs with longer in vivo half-lives are highly desirable. One of the most promising approaches to extend the in vivo half-life of drugs is conjugation to human serum albumin (HSA). In this work, we describe the use of AlbuBinder 1, a small-molecule noncovalent HSA binder, to extend the in vivo half-life and pharmacology of small-molecule BMP1/TLL inhibitors in humanized mice (HSA KI/KI). A series of conjugates of AlbuBinder 1 with BMP1/TLL inhibitors were prepared. In particular, conjugate c 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 AlbuBinder 1 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.

中文翻译:

使用小分子人血清白蛋白结合剂延长 BMP1/TLL 金属蛋白酶抑制剂的体内半衰期

降低所需的药物给药频率可以提高患者对长期治疗的依从性。因此,具有较长体内半衰期的药物是非常可取的。延长药物体内半衰期的最有希望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 结合剂AlbuBinder 1来延长小分子 BMP1/TLL 抑制剂在人源化小鼠 (HSA KI/KI)中的体内半衰期和药理学。制备了一系列AlbuBinder 1与 BMP1/TLL 抑制剂的偶联物。特别是,共轭 c在 HSA KI/KI 小鼠中,与母体分子相比,它显示出良好的溶解性和 20 倍以上的半衰期延长,达到了 >48 小时的半衰期,并保持了对血浆 BMP1/TLL 的最大抑制。相同的偶联物在野生型小鼠中的半衰期仅为 3 小时,这表明半衰期延长主要是由于与 HSA 的特定相互作用。预计与AlbuBinder 1 的结合应该适用于范围广泛的小分子或短半衰期的肽药物。在这种情况下,AlbuBinders 代表了现有半衰期延长技术的可行替代方案。
更新日期:2021-02-17
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