We modified amylin chemically by conjugating methoxyl polyethyleneglycol succinimidyl carbonate (mPEGSC)
of varying molecular weights (1 kDa, 2 kDa and 5 kDa). The reaction occurred within a few minutes, resulting in at
least four distinct PEGylated products. The reaction products were separated by reversed-phase chromatography and identified
by mass-spectrometry. The monoPEGylated and diPEGylated amylin products were generated rapidly through conjugation
to the two amino groups of the N-terminal lysine residue. Both PEGylated amylin products bound to the receptor
activity-modifying protein 1 (RAMP1). Pharmacological evaluation by subcutaneous administration in mice of monoPEGylated
and diPEGylated amylin obtained with mPEG-SC 5 kDa revealed that both compounds modulated glycemia
for longer times than unmodified amylin. Collectively, these data demonstrate the potential of bioconjugation with mPEG
for the design of amylin therapeutics with sustained action.
Keywords: Amylin, diabetes, glycemia, islet associated polypeptide, PEGylation.
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