posted on 2021-02-01, 18:40authored byJulien
C. Vantourout, Andrew M. Mason, Josephine Yuen, Graham L. Simpson, Ghotas Evindar, Letian Kuai, Michael Hobbs, Emma Edgar, Saul Needle, Xiaopeng Bai, Steve Wilson, Paul Scott-Stevens, William Traylen, Kim Lambert, Neil Young, Shenaz Bunally, Scott G. Summerfield, Richard Snell, Rakesh Lad, Eric Shi, Steven Skinner, Lisa Shewchuk, Allan J.B. Watson, Chun-wa Chung, Sandeep Pal, Dennis A. Holt, Lara S. Kallander, Joanne Prendergast, Katrina Rivera, David G. Washburn, Mark R. Harpel, Christopher Arico-Muendel, Albert Isidro-Llobet
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.