| Autor: |
Vantourout, Julien C., Mason, Andrew M., Yuen, Josephine, Simpson, Graham L., Evindar, Ghotas, Kuai, Letian, Hobbs, Michael, Edgar, Emma, Needle, Saul, Bai, Xiaopeng, Wilson, Steve, Scott-Stevens, Paul, Traylen, William, Lambert, Kim, Young, Neil, Bunally, Shenaz, Summerfield, Scott G., Snell, Richard, Lad, Rakesh, Shi, Eric, Skinner, Steven, Shewchuk, Lisa, Watson, Allan J.B., Chung, Chun-wa, Pal, Sandeep, Holt, Dennis A., Kallander, Lara S., Prendergast, Joanne, Rivera, Katrina, Washburn, David G., Harpel, Mark R., Arico-Muendel, Christopher, Isidro-Llobet, Albert |
| Zdroj: |
Bioconjugate Chemistry; 20210101, Issue: Preprints |
| Abstrakt: |
Reducing the required frequence of drug dosing can improve the adherence of patients to chronic treatments. Hence, drugs with longer in vivohalf-lives are highly desirable. One of the most promising approaches to extend the in vivohalf-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 vivohalf-life and pharmacology of small-molecule BMP1/TLL inhibitors in humanized mice (HSA KI/KI). A series of conjugates of AlbuBinder 1with BMP1/TLL inhibitors were prepared. In particular, conjugate cshowed 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 1should 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: |
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