A new class of immunotherapeutic drugs will be designed around the IiKEY peptide to enhance or inhibit, in an MHC class II allele related manner, immune responses in several disease states. Binding of IiKEY homologs at an allosteric site alongside one end of the antigenic peptide binding groove of MHC class II molecules, induces a structural change in the MHC class II molecule to release bound peptides and to enhance charging with other immunogenic peptides. T hybridoma responses to those added, specific antigenic peptides are enhanced 16 to 20 times above the baseline levels. The IiKEY sequence is in the last segment of the Ii protein to be released from MHC Class II molecules during the staged cleavage and release of Ii by cathepsins B and D. The minimal fully active core of IiKEY lies immediately to the N-terminus of the aii-CLIP sequence which Ghosh, Mellins and Wiley ( Nature, in press) have shown to lie the antigenic binding groove as a type II polyprolyl helix (exactly in the position of he influenza HA-2 antigenic peptide). The IiKEY site is thus a novel allosteric target for drug design, suitable for attack by rational drug design based on the IiKEY sequence. Through this Phase I SBIR, we seek to increase the in vitro potency of peptide homologs to 1-10 nM (from 1-4(mu)M) and to protect the backbone from hydrolysis for subsequent in vivo studies. Optimal IiKEY peptide homologs will be selected by testing potencies of 1) acetylated and amidated peptides, 2) N-and C-terminal deletion and then the shortest active segment of IiKEY, 3)systematic alanine substitutions at each residue positive to identify residues required for biological activity, 4) systematic replacements with a series of natural, and eventually with D-amino acids and other nonnatural amino acids at residue positions critical for biological activity 5)systematic backbone modifications to protect against hydrolysis, and 6) ring structure stabilizations. The best """"""""drug leads"""""""" will be tested in animal studies of peptide vaccination, EAE and collagen arthritis.
Potent, small peptide homologs or peptidomimetics of the IiKEY acting at an allosteric site along one end of MHC class II antigenic peptide binding site are drug leads of a new class of immunotherapeutics to control autoimmune disease, and enhance peptide vaccinations, or control allergies.
|Xu, M; Li, J; Gulfo, J V et al. (2001) MHC class II allosteric site drugs: new immunotherapeutics for malignant, infectious and autoimmune diseases. Scand J Immunol 54:39-44|