In Vivo Half-Life Extension of BMP1/TLL Metalloproteinase Inhibitors Using Small-Molecule Human Serum Albumin Binders.

Autor:	Vantourout JC; GlaxoSmithKline U.K., Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.; Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G11XL, U.K., Mason AM; GlaxoSmithKline U.K., Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K., Yuen J; GlaxoSmithKline US, 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, United States., Simpson GL; GlaxoSmithKline U.K., Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K., Evindar G; GlaxoSmithKline US, 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, United States., Kuai L; GlaxoSmithKline US, 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, United States., Hobbs M; GlaxoSmithKline U.K., Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K., Edgar E; GlaxoSmithKline U.K., Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K., Needle S; GlaxoSmithKline US, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States., Bai X; GlaxoSmithKline US, 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, United States., Wilson S; GlaxoSmithKline U.K., Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K., Scott-Stevens P; GlaxoSmithKline U.K., Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K., Traylen W; GlaxoSmithKline U.K., Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K., Lambert K; GlaxoSmithKline U.K., Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K., Young N; GlaxoSmithKline U.K., Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K., Bunally S; GlaxoSmithKline U.K., Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K., Summerfield SG; GlaxoSmithKline U.K., Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K., Snell R; GlaxoSmithKline U.K., Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K., Lad R; GlaxoSmithKline U.K., Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K., Shi E; GlaxoSmithKline US, 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, United States., Skinner S; GlaxoSmithKline US, 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, United States., Shewchuk L; GlaxoSmithKline US, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States., Watson AJB; University of St Andrews, North Haugh, St Andrews KY16 9ST, U.K., Chung CW; GlaxoSmithKline U.K., Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K., Pal S; GlaxoSmithKline U.K., Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K., Holt DA; GlaxoSmithKline US, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States., Kallander LS; GlaxoSmithKline US, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States., Prendergast J; GlaxoSmithKline US, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States., Rivera K; GlaxoSmithKline US, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States., Washburn DG; GlaxoSmithKline US, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States., Harpel MR; GlaxoSmithKline US, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States., Arico-Muendel C; GlaxoSmithKline US, 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, United States., Isidro-Llobet A; GlaxoSmithKline U.K., Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
Jazyk:	angličtina
Zdroj:	Bioconjugate chemistry [Bioconjug Chem] 2021 Feb 17; Vol. 32 (2), pp. 279-289. Date of Electronic Publication: 2021 Feb 01.
DOI:	10.1021/acs.bioconjchem.0c00662
Abstrakt:	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.
Databáze:	MEDLINE
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