期刊
MOLECULAR PHARMACEUTICS
卷 -, 期 -, 页码 -出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.molpharmaceut.2c00106
关键词
CuAAC; helix; loop; helix; insulin; serum albumin; yeast surface display
The effectiveness of protein and peptide pharmaceuticals depends on their pharmacokinetics. Small-sized pharmaceuticals often have short half-lives due to rapid renal clearance. Researchers have developed a helix-loop-helix peptide binding tag to improve pharmacokinetics by associating with serum albumin. The tag has the potential to extend the bioactivity of therapeutic peptides or proteins.
The effectiveness of protein and peptide pharmaceuticals depends essentially on their intrinsic pharmacokinetics. Small-sized pharmaceuticals in particular often suffer from short serum half-lives due to rapid renal clearance. To improve the pharmacokinetics by association with serum albumin (SA) in vivo, we generated an SA-binding tag of a helix-loop-helix (HLH) peptide to be linked with protein pharmaceuticals. For use in future preclinical studies, screening of yeast-displayed HLH peptide libraries against human SA (HSA) and mouse SA (MSA) was alternately repeated to give the SA-binding peptide AY-VE, which exhibited cross-binding activities to HSA and MSA with KD of 65 and 20 nM, respectively. As a proof of concept, we site-specifically conjugated peptide AY-VE with insulin to examine its bioactivity in vivo. In mouse bioassay monitoring the blood glucose level, the AY-VE conjugate was found to have a prolonged hypoglycemic effect for 12 h. The HLH peptide tag is a general platform for extending the bioactivity of therapeutic peptides or proteins.
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