Document Type


Publication Date


Publication Title

Peptide Science





First Page



unnatural amino acids, altered peptide ligands, autoimmune disease, multiple sclerosis, celiac disease, rheumatoid arthritis


Many autoimmune diseases, including multiple sclerosis (MS), rheumatoid arthritis (RA), and celiac disease (CD), arise from improper immune system recognition of self or benign peptides as threats. No autoimmune disease currently has a cure. Many treatments suppress the entire immune system to decrease symptom severity. The core molecular interaction underlying these diseases involves specific alleles of the human leukocyte antigen (HLA) receptor hosting the immunodominant peptides associated with the disease (i.e. myelin basic protein, Type II collagen, or α-gliadin) in their binding groove. Once bound, circulating T-cells can recognize the HLA-antigen complex and initiate the complex cascade that forms an adaptive immune response. This initial HLA-antigen interaction is a promising target for therapeutic intervention. Two general strategies have been pursued: altered peptide ligands (APLs) that attempt to recruit a different class of T-cell to induce an anti-inflammatory response to balance the pro-inflammatory response associated with the antigen; and HLA blockers (HLABs), peptides that, due to a much higher affinity for the HLA receptor, quantitatively displace the antigen, inhibiting the immune response. Both approaches would benefit from improved HLA-drug binding, but as the HLA receptors are highly promiscuous, the binding sites are not specific for any natural amino acid. Unnatural amino acids, either designed or screened through high-throughput assays, may provide a solution. This review summarizes the nascent field of using non-canonical residues to treat MS, RA and CD, focusing on the importance of specific molecular interactions, and provides some examples of the synthesis of these unnatural residues.



Funding Reference Number

University of Windsor, 817074