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• W2332314894 abstract "Clinically used peptides and antibodies can be modified to improve their therapeutic potential. As peptides are relatively small molecules, they display rapid renal clearance. Modifying a peptide by conjugation to poly(ethylene glycol) (PEG) or a protein carrier, such as an antibody are clinically valid examples to make peptides therapeutically more efficacious. Peptide modification using an efficient site-selective conjugation strategy is required to prepare homogenous conjugates that if efficacious, then have the potential for development. Mono-thiol specific conjugation can be accomplished using maleimide reagents. However, maleimide based conjugates are prone to de-conjugation or exchange reactions with plasma proteins. To address this limitation a mono-sulfone PEG reagent 1 that can undergo efficient conjugation to a single cysteine thiol in a therapeutic peptide that had been developed has been evaluated with peptides. In contrast to maleimide derived conjugates, any resulting conjugate from reagent 1 can be further stabilised with sodium borohydride to prevent PEG de-conjugation by a retro-Michael reaction. A dual-agonist peptide, PEP5 underwent conjugation with reagent 1 derived from a 40 kDa PEG with 90% conversion to give the PEG40-PEP5 conjugate. The pure conjugate was obtained in 50% yield after purification by ion exchange chromatography (IEX). An in vitro receptor binding assay showed that the PEG40-PEP5 conjugate displayed 0.11-4% and 0.08-2.2% binding affinities against two relevant receptors. A mouse PK study showed the PEG40-PEP5 conjugate had a 60-fold improved circulation time (15.9 h) compared to the non-modified PEP5 (0.26 h) while also reducing blood glucose levels in obese mice. Conjugation by bis-alkylation to the two thiols that are derived from a disulfide bond is another efficient way to prepare stable and homogenous PEG-peptide conjugates. The thiol bis-alkylating PEG reagent 3 can selectively alkylate both sulfurs derived from a naturally occurring disulfide bond to form a conjugate with a three-carbon bridge between the two cysteine thiols. Octreotide (OCT) is a cyclic octapeptide with a disulfide that underwent reaction at the two cysteine thiols with the 10 kDa PEG variant of reagent 3 at 78% conversion to give a PEG10-OCT conjugate. The PEG10-OCT conjugate maintained its selectivity towards somatostatin receptor 2 (sst2) and 5 (sst5) in an in vitro receptor-binding assay. A molecular dynamics (MD) study showed that insertion of the three-carbon bridge between the cysteine thiols maintained the active structure of OCT responsible for the interactions with the somatostatin receptors. PEG10-OCT also displayed a significant inhibitory effect on IGF-1 at 24 and 48 h in an in vivo study while displaying a longer in vivo circulation time than the non-modified OCT at the same 0.3 mg/kg dose. The PEG10-OCT was detected at average 43 ng/mL and 55 ng/mL at 4 h and 8 h respectively, while OCT was below the detection limit ( 99% efficiency. The functionalised beads allowed a 80% recovery of trastuzumab-PEG(24u)-val-cit-PAB-MMAE conjugate from mouse serum. The DAR profile of the purified ADC conjugate was assessed by HIC and showed there was drug loss (~30%) possibly being due to instability of the val-cit-PAB cleavable linker in blood circulation but not de-conjugation as shown by mass spectrometry analysis." @default.
• W2332314894 created "2016-06-24" @default.
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• W2332314894 date "2015-09-28" @default.
• W2332314894 modified "2023-09-24" @default.
• W2332314894 title "Site-specific peptide conjugation to carrier molecules" @default.
• W2332314894 hasPublicationYear "2015" @default.
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