Rational design of a Tn antigen mimic

Abstract

A novel Tn antigen mimic, in which the natural underlying amino acid has been replaced by the non-natural α-methylserine analogue, is reported. This derivative exhibits a similar affinity for a natural lectin as for the natural Tn and retains the bioactive conformation observed in the Tn-containing glycopeptides with anti-MUC1 antibodies.

Sugar‐Modified Foldamers as Conformationally Defined and Biologically Distinct Glycopeptide Mimics

“…[1] Considerable effort has thus been invested in delineating the impact of appended carbohydrates on the conformational preferences of proteins and peptides in solution and vice versa, [2] and also in understanding their interactions with their cognate receptors. [3] These endeavours are not straightforward, and success in rationalizing such processes has been possible only in a handful of well-studied cases. [4] Important insights into such questions have been gleaned from the study of glycoconjugate mimetics, whose interactions with cellular targets can impact a wide range of physiological phenomena, including fertilization, immune response, host–pathogen interactions, cell growth, and tumor metastasis.…”

A Synthetic MUC1 Glycopeptide Bearing βGalNAc‐Thr as a Tn Antigen Isomer Induces the Production of Antibodies against Tumor Cells

“…Accordingly, new synthetic methods for obtaining Tn antigen as well as its counterpart analogues have been constantly investigated . To date, several Tn antigen analogues have been reported for use as vaccine constructs; examples include C‐glycosides, S‐glycosides, deoxyfluoro sugars, and Tn glycopeptide mimics containing unnatural amino acids . C‐glycosides and S‐glycosides are more stable toward enzymatic and chemical hydrolysis than natural Tn, because they have the interglycosidic oxygen atom replaced by a methylene group or by a sulfur atom, respectively .…”

“…Deoxyfluoro‐Tn analogues, possessing a fluorine atom instead of a sugar hydroxy group, are believed to enhance the immunogenicity of the antigen, as fluorine is absent in most organisms, as well as its bioavailability . The use of unnatural amino acids, such as α‐methylserine, or others containing long aliphatic side chains, has proven to be effective for obtaining unnatural Tn peptide‐linked vaccines with improved immunogenicity . The application of Cu I ‐assisted 1,3‐dipolar azide–alkyne cycloaddition (CuAAC) reactions between propargylated α‐GalNAc sugar and azido‐functionalized amino acids, or vice versa, represents another strategy for the synthesis of triazole‐derived Tn neoglycopeptide vaccines with advantageous physicochemical properties inherent to the triazole group …”

“…As judged from its structural similarity to Tn antigen, differing only in the anomeric configuration, βGalNAc‐Ser/Thr could be a frontline building block for development of antitumor vaccines, depending on its efficiency for inducing active immunity. In this regard, the crystal structure of the antitumor monoclonal antibody SM3 (SM3 mAb), which is able to recognize the fundamental epitope of the MUC1 peptide (SAPDTRPAP) and the corresponding glycopeptide [SAPDT( O ‐αGalNAc)RPAP], might represent a model for theoretical investigations of the βGalNAc‐Ser/Thr core as a new Tn mimic …”

Protein Engineering with Non-Natural Amino Acids

“…This may be of special importance to peptide-based vaccines due to the short half-life of peptides. Peptides designed with NNAAs may adopt bioactive conformation with enhanced stability, and thus elicit immune response to wild-type tumor antigens (Vichier-Guerre et al, 2004;Corzana et al, 2011).…”