Vantourout JC, Mason AM, Yuen J, Simpson GL, Evindar G, Kuai L, Hobbs M, Edgar E, Needle S, Bai X, Wilson S, Scott-Stevens P, Traylen W, Lambert K, Young N, Bunally S, Summerfield SG, Snell R, Lad R, Shi E, Skinner S, Shewchuk L, Watson AJB, Chung CW, Pal S, Holt DA, Kallander LS, Prendergast J, Rivera K, Washburn DG, Harpel MR, Arico-Muendel C, and Isidro-Llobet A
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.