N-Amino-imidazol-2-one (Nai) Residues as Tools for Peptide Mimicry: Synthesis, Conformational Analysis and Biomedical Applications

N-Amino-imidazol-2-one (Nai) residues are tools for studying peptide-backbone and side-chain conformation and function. Recent methods for substituted Nai residue synthesis, conformational analysis by X-ray crystallography and computation, and biomedical applications are reviewed, demonstrating the utility of this constrained residue to favor biologically active turn conformers with defined χ-dihedral angle orientations.1 Introduction2 Synthetic Methods3 Conformational Analysis4 Biomedical Applications5 Conclusions

Constrained Dipeptide Surrogates: 5- and 7-Hydroxy Indolizidin-2-one Amino Acid Synthesis from Iodolactonization of Dehydro-2,8-diamino Azelates

The constrained dipeptide surrogates 5- and 7-hydroxy indolizidin-2-one N-(Boc)amino acids have been synthesized from L-serine as a chiral educt. A linear precursor ∆4-unsaturated (2S,8S)-2,8-bis[N-(Boc)amino]azelic acid was prepared in five steps from L-serine. Although epoxidation and dihydroxylation pathways gave mixtures of hydroxy indolizidin-2-one diastereomers, iodolactonization of the ∆4-azelate stereoselectively delivered a lactone iodide from which separable (5S)- and (7S)-hydroxy indolizidin-2-one N-(Boc)amino esters were synthesized by sequences featuring intramolecular iodide displacement and lactam formation. X-ray analysis of the (7S)-hydroxy indolizidin-2-one N-(Boc)amino ester indicated that the backbone dihedral angles embedded in the bicyclic ring system resembled those of the central residues of an ideal type II’ β-turn indicating the potential for peptide mimicry.

Benchmarking evolutionary tinkering underlying human–viral molecular mimicry shows multiple host pulmonary–arterial peptides mimicked by SARS-CoV-2

The hand of molecular mimicry in shaping SARS-CoV-2 evolution and immune evasion remains to be deciphered. Here, we report 33 distinct 8-mer/9-mer peptides that are identical between SARS-CoV-2 and the human reference proteome. We benchmark this observation against other viral–human 8-mer/9-mer peptide identity, which suggests generally similar extents of molecular mimicry for SARS-CoV-2 and many other human viruses. Interestingly, 20 novel human peptides mimicked by SARS-CoV-2 have not been observed in any previous coronavirus strains (HCoV, SARS-CoV, and MERS). Furthermore, four of the human 8-mer/9-mer peptides mimicked by SARS-CoV-2 map onto HLA-B*40:01, HLA-B*40:02, and HLA-B*35:01 binding peptides from human PAM, ANXA7, PGD, and ALOX5AP proteins. This mimicry of multiple human proteins by SARS-CoV-2 is made salient by single-cell RNA-seq (scRNA-seq) analysis that shows the targeted genes significantly expressed in human lungs and arteries; tissues implicated in COVID-19 pathogenesis. Finally, HLA-A*03 restricted 8-mer peptides are found to be shared broadly by human and coronaviridae helicases in functional hotspots, with potential implications for nucleic acid unwinding upon initial infection. This study presents the first scan of human peptide mimicry by SARS-CoV-2, and via its benchmarking against human–viral mimicry more broadly, presents a computational framework for follow-up studies to assay how evolutionary tinkering may relate to zoonosis and herd immunity.

Multi-pronged human protein mimicry by SARS-CoV-2 reveals bifurcating potential for MHC detection and immune evasion

The hand of molecular mimicry in shaping SARS-CoV-2 evolution and immune evasion remains to be deciphered. We identify 33 distinct 8-mer/9-mer peptides that are identical between SARS-CoV-2 and human proteomes, along similar extents of viral mimicry observed in other viruses. Interestingly, 20 novel peptides have not been observed in any previous human coronavirus (HCoV) strains. Four of the total mimicked 8-mers/9-mers map onto HLA-B*40:01, HLA-B*40:02, and HLA-B*35:01 binding peptides from human PAM, ANXA7, PGD, and ALOX5AP proteins. This mimicry of multiple human proteins by SARS-CoV-2 is made salient by the targeted genes being focally expressed in arteries, lungs, esophagus, pancreas, and macrophages. Further, HLA-A*03 restricted 8-mer peptides are shared broadly by human and coronaviridae helicases with primary expression of the mimicked human proteins in the neurons and immune cells. This study presents the first comprehensive scan of peptide mimicry by SARS-CoV-2 of the human proteome and motivates follow-up research into its immunological consequences.

Peripheral tolerance to insulin is encoded by mimicry in the microbiome

How organisms achieve sustained peripheral tolerance throughout their lifetime, a correct immune discrimination between self and non-self, remains poorly understood. Host-microbiome interactions carry fundamental information that facilitates this process. We hypothesize that commensal microbes are under evolutionary pressure to develop epitopes that, when presented along with other antigens from their own bacterial community, lead to an overall tolerogenic self classification by the host immune system. Hosts, which have co-evolved with commensals, may rely on mimotopes, bacterial epitopes that are indistinguishable from key self epitopes, as a homeostatic feedback mechanism to establish and maintain tolerance. Using a probabilistic sequence model of peptide mimicry, we show that the gut microbiome contains a set of genes that are likely to trigger identical immune responses to insulin B 9–25, a widely distributed self epitope across tissues and the primary autoantigen in type 1 diabetes. Similarities in the antigen receptor sequences determined from CD4 T cells reacting to insulin epitopes and mimotopes provide experimental evidence for mimicry. All predicted high posterior probability mimotopes belong to the transketolase superfamily, an enzyme that allows efficient harvest of commensal-derived sugar polymers and dietary fibre, an advantage during host colonisation. Microbial transketolase upregulation during infant weaning coincides in time with the peak in autoantibody development against insulin. Abundance changes in bacterial genera that carry these mimotopes have also been observed to precede disease diagnosis. Our findings suggest gut dysbiosis followed by immune response to insulin mimotopes as a primary cause of type 1 diabetes, and may contribute towards unraveling similar causal patterns in a wide variety of disorders.

Bioinspired Polymers: Antimicrobial Polymethacrylates

Naturally occurring antimicrobial peptides have been honed by evolution over millions of years to give highly safe and efficacious antimicrobials that form part of many organisms’ immune systems. By studying these peptides to identify key aspects of structure and composition, suitable synthetic polymer mimics can be designed that hold potential as anti-infective agents. This review focusses on an important aspect of peptide mimicry, that of replicating the chemical functionality provided by key amino acids present in antimicrobial peptides. These include polymethacrylate mimics of arginine-rich and tryptophan-rich peptides. Systematic investigation of the structure–activity relationships of these polymers identifies the guanidine based poly(methylmethacrylate-co-2-guanidinoethyl methacrylate) (pMMA-co-GEMA) copolymers with low molecular weight and low methyl content as having superior activity profiles when compared with all other combinations. Unique antibiofilm activity of these polymers is also revealed in in vitro testing against monomicrobial and polymicrobial biofilms of the bacteria Staphylococcus aureus and the fungus Candida albicans. This highlights Mother Nature as an important resource in drug development and identifies the arginine-mimicking polymethacrylates as important leads for the development of a new generation of antimicrobial agents to tackle resistance.