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Research at St Andrews

In vivo half-life extension of BMP1/TLL metalloproteinase inhibitors using small-molecule human serum albumin binders

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Author(s)

Julien 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 & 13 more 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

School/Research organisations

Abstract

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.
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Details

Original languageEnglish
JournalBioconjugate Chemistry
Volume32
Issue number2
DOIs
Publication statusPublished - 17 Feb 2021

    Research areas

  • Half-life, Peptides and proteins, Rodents models, Biopolymers, Conjugate acid-base pairs

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