Glycosylation, an effective synthetic strategy to improve the bioavailability of therapeutic peptides

Abstract

Glycosylation of peptides is a promising strategy for modulating the physicochemical properties of peptide drugs and for improving their absorption through biological membranes.

OleD Loki as a Catalyst for Tertiary Amine and Hydroxamate Glycosylation

“…Although tertiary-amine N-glucuronidation has been reported in the context of phase II metabolism, [10] fundamental biochemical study of the corresponding glucuronsyltransferases has been hampered by limited access to suitable in vitro models. Likewise, although sugar conjugation is known to influence small-molecule mechanisms, potency, and ADMET, [1a, e, 20] a lack of practical synthetic or chemoenzymatic access has limited studies to probe the fundamental properties of quaternary N-glycosides. [10,11] Our discovery offers a convenient new model for GT-catalyzed tertiary-amine N-glycosylation and a potential complementary synthetic platform for efficient one-step synthesis of quaternary N-glycosides.…”

Orally Active Peptides: Is There a Magic Bullet?

“…[86] On the other hand, reports indicate the participation of at ransporter, suggested by different uptake rates of cyclic hexaalanine enantiomers,which indicates the participation of achiral structural element in their transport and different flux ratios in Caco-2 membranes. [126] As tudy of af urther refunctional- hiding side-chain polarity i) Thr is apolar amino acid that is well-tolerated in bioavailable peptides [99a,116] ii)replacementofThr by Ser led to decreased permeability and, thus, the b-methyl group seems to orient the hydroxy group to form an intramolecular hydrogen bond and to shield the polarity iii)2-pyridinealanine can hide the side-chain polarity in amanner similar to Thr, [155] but attempts to modify permeable cyclic peptides resulted in lower permeability [150] [99a, 116] exocyclic peptide bond i) introducedbyaziridine-aldehyde-based macrocyclization, followed by nucleophilic attack by isocyanide and hydrolysis [118] ii)used to optimize the hydrogen bonding network, thereby reducing the polarity and flexibility of ap eptide iii)has aturn-inducing effect [107b] [118] lipophilic prodrug charge masking (LPCM) approach i) shields charges through esterase-labile protecting groups that enable uptake of the peptide [119] ii)prodrug concepts for cyclizing peptides, which release alinear peptide after cleavage, have been developed [156] iii)positive and negative charges can be protectedbyenzymatically labile groups, such as in arecently publishedc yclic peptide (24) iv) the biologically active compound is releasedi nto the blood stream and can bind to surface receptors, such as integrins; [115] this concept was adopted for cyclic peptides derived from dabigatran [157] [ 115,156] lipidation i) increases lipophilicity through aliphaticc hains ii)increases plasma stability iii)binds to serum albumin, prolongingthe duration of systemic circulation [158] iv) forms self-assembling oligomeric macromolecules, enhances enzymatic degradation [159] v) its effect on bioavailability strongly depends on the fatty acid chain length [160] vi)t he modification with amyristoyl group (n = 12) improved the oral bioavailability of the peptide c(MyD 4-4) by af actor of > 50 to F = 47 AE 16 % [161] [162] glycosylation i) affects the backbone structure of peptides [163] ii)improves half-life against enzymatic degradation [164] iii)glycosylated sandostatin (d(+)-maltose) shows a10-fold greater oral effect than the nonglycosylated derivative [165] iv) glycosylated endomorphin-1 (27)s hows a700-fold increase in memb...…”

“…: c(*aAAAA*A) (14) c(*aAAA*AA) (15) c(*a*AA*A*AA) (16) cyclization, N-methylation, 2 b-turns, cis-peptide bond (2 of 3) no PAMPA permeability [167] P app % 20 10 À6 cm s À1 (Caco-2) [167] [ [110] F = 21 AE 3% [112] F = 60 %(with microemulsion formulation) [168] comment:bioavailability strongly dependso nthe formulation and patients [127,169] tri-N-methylated Veber-Hirschmann peptide Angewandte Chemie Reviews microemulsion formulation that leads to ab ioavailability of 60 %w ith relatively low variability. [168] Thecomplexity of the mechanism of this natural product is unique and has become the predominant model for research on peptide bioavailability.C sA (17)c ombines av ariety of features that enhance oral bioavailability.H owever,i ts eems too complicated with current technology to mimic the interesting cis-trans interconversion as ar ational [164,166] [a] Strongly depends on the patient.…”

Synthesis, Characterization and Immunological Evaluation of Self‐Adjuvanting Group A Streptococcal Vaccine Candidates Bearing Various Lipidic Adjuvanting Moieties

“…), DIPEA (4.6 equiv.). Following piperidine deprotection of the N terminus, the TPGlc (2,3,4,6-tetra-O-acetyl-1-O-(6-methoxy-6-oxohexyl)-β-D-glucopyranose) 12 carbohydrate building block (2.5 equiv. in 1 mL of DMF) and DIPEA (4.6 equiv.)…”

“…12 The sequence was capped using standard acetylation conditions. Following cleavage from the resin and precipitation, the crude glyco-lipopeptide 3c was dissolved in a minimum volume of DMF, diluted with solvent A and B (1:1, 50 mL), and lyophilized.…”