Journal
MOLECULES
Volume 23, Issue 2, Pages -Publisher
MDPI
DOI: 10.3390/molecules23020304
Keywords
myelin basic protein (MBP); experimental autoimmune encephalomyelitis (EAE); multiple sclerosis (MS); altered peptide ligands (APLs); cyclic peptides
Funding
- European Commission through the NeuroSign project FP7 REGPOT grant [264083]
- Hellenic Republic Ministry of Education-General Secretariat of Research & Technology (GSRT) through the National Action Cooperation project grant Multiple Sclerosis Therapy [09SYN-21-609]
- Bilateral R&T Greece-Israel Collaboration grant A novel combined approach for the immunotherapy of multiple sclerosis [ISR_3148]
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In this report, amide-linked cyclic peptide analogues of the 87-99 myelin basic protein (MBP) epitope, a candidate autoantigen in multiple sclerosis (MS), are tested for therapeutic efficacy in experimental autoimmune encephalomyelitis (EAE). Cyclic altered peptide analogues of MBP87-99 with substitutions at positions 91 and/or 96 were tested for protective effects when administered using prophylactic or early therapeutic protocols in MBP72-85-induced EAE in Lewis rats. The Lys(91) and Pro(96) of MBP87-99 are crucial T-cell receptor (TCR) anchors and participate in the formation of trimolecular complex between the TCR-antigen (peptide)-MHC (major histocompability complex) for the stimulation of encephalitogenic T cells that are necessary for EAE induction and are implicated in MS. The cyclic peptides were synthesized using Solid Phase Peptide Synthesis (SPPS) applied on the 9-fluorenylmethyloxycarboxyl/tert-butyl Fmoc/tBu methodology and combined with the 2-chlorotrityl chloride resin (CLTR-Cl). Cyclo(91-99)[Ala(96)] MBP87-99, cyclo(87-99)[Ala(91,96)] MBP87-99 and cyclo(87-99)[Arg(91), Ala(96)] MBP87-99, but not wild-type linear MBP87-99, strongly inhibited MBP72-85-induced EAE in Lewis rats when administered using prophylactic and early therapeutic vaccination protocols. In particular, cyclo(87-99)[Arg(91), Ala(96)] MBP87-99 was highly effective in preventing the onset and development of clinical symptoms and spinal cord pathology and providing lasting protection against EAE induction.
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