TY - JOUR
T1 - In vivo half-life extension of BMP1/TLL metalloproteinase inhibitors using small-molecule human serum albumin binders
AU - Vantourout, Julien C
AU - Mason, Andrew M
AU - Yuen, Josephine
AU - Simpson, Graham L
AU - Evindar, Ghotas
AU - Kuai, Letian
AU - Hobbs, Michael
AU - Edgar, Emma
AU - Needle, Saul
AU - Bai, Xiaopeng
AU - Wilson, Steve
AU - Scott-Stevens, Paul
AU - Traylen, William
AU - Lambert, Kim
AU - Young, Neil
AU - Bunally, Shenaz
AU - Summerfield, Scott G
AU - Snell, Richard
AU - Lad, Rakesh
AU - Shi, Eric
AU - Skinner, Steven
AU - Shewchuk, Lisa
AU - Watson, Allan J B
AU - Chung, Chun-Wa
AU - Pal, Sandeep
AU - Holt, Dennis A
AU - Kallander, Lara S
AU - Prendergast, Joanne
AU - Rivera, Katrina
AU - Washburn, David G
AU - Harpel, Mark R
AU - Arico-Muendel, Christopher
AU - Isidro-Llobet, Albert
N1 - We thank the GlaxoSmithKline/University of Strathclyde Collaborative Ph.D. programme for funding this work (to J.C.V., Ph.D. studentship).
PY - 2021/2/17
Y1 - 2021/2/17
N2 - 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.
AB - 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.
KW - Half-life
KW - Peptides and proteins
KW - Rodents models
KW - Biopolymers
KW - Conjugate acid-base pairs
U2 - 10.1021/acs.bioconjchem.0c00662
DO - 10.1021/acs.bioconjchem.0c00662
M3 - Article
C2 - 33523652
SN - 1043-1802
VL - 32
JO - Bioconjugate Chemistry
JF - Bioconjugate Chemistry
IS - 2
ER -