Design and synthesis of a potent cyclic analogue of the myelin basic protein epitope MBP72-85: Importance of the Ala(81) carboxyl group and of at cyclic conformation for induction of experimental allergic encephalomyelitis
Φόρτωση...
Ημερομηνία
Συγγραφείς
Tselios, T.
Probert, L.
Daliani, I.
Matsoukas, E.
Troganis, A.
Gerothanassis, I. P.
Mavromoustakos, T.
Moore, G. J.
Matsoukas, J. M.
Τίτλος Εφημερίδας
Περιοδικό ISSN
Τίτλος τόμου
Εκδότης
American Chemical Society
Περίληψη
Τύπος
Είδος δημοσίευσης σε συνέδριο
Είδος περιοδικού
peer reviewed
Είδος εκπαιδευτικού υλικού
Όνομα συνεδρίου
Όνομα περιοδικού
J Med Chem
Όνομα βιβλίου
Σειρά βιβλίου
Έκδοση βιβλίου
Συμπληρωματικός/δευτερεύων τίτλος
Περιγραφή
Experimental allergic encephalomyelitis (EAE) is induced in susceptible animals by immunodominant determinants of myelin basic protein (MBP), such as guinea pig sequence MBP72-85. Two linear and one cyclic analogues based on MBP72-85 have been synthesized and evaluated for EAE induction in Lewis rats. The line ar peptide Gln(1)-Lys-(2)Ser(3)-Gln(4)-Arg(5)-Ser(6)-Gln(7)-Asp(8)-Glu(9)-Asn(10)-Pro(11)-Val(12) (1) was found to induce EAE, while substitution of the Asp residue at position 8 with Ala resulted in an analogue (2) which suppressed the induction of EAE by its parent peptide. Nuclear magnetic resonance studies of analogue 1 in dimethyl sulfoxide (DMSO) using TOCSY/ROESY techniques revealed a head-to-tail intramolecular interaction (ROE connectivity between beta Val(12)-gamma Gln(1)), indicating a pseudocyclic conformation for the immunogenic peptide 1. A conformational model was developed using NMR constraints and molecular dynamics. Based on this model, a novel amide-linked cyclic analogue has been designed and synthesized by connecting the side-chain amino and carboxyl groups of Lys and Glu at positions 2 and 9, respectively, of linear analogue 1. The cyclic analogue Gln-Lys-Ser-GLn-Arg-Ser-Gln-Asp-Glu-Asn-Pro-Val-NH2 (3) had similar activity to the linear peptide 1, and the EAE effects induced by cyclic analogue 3 Were completely suppressed by co;injection with the Ala(81)-substituted analogue 2 in Lewis rats. The similar potencies of analogues 1 and 3 support the proposed cyclic comformation suggested for analogue-1 from NMR studies and computer modeling and provides the basis for designing more potent molecules with improved properties such as increased resistance:,to degradation.(15) The present findings suggest that a cyclic conformation for the MBP72-85 epitope positions the carboxyl group of Asp(81) correctly and presumably other side groups of the peptide such as Arg(78) in a manner which enables functional binding of the trimolecular complex MHC-peptide-T cell receptor resulting in EAE.
Περιγραφή
Λέξεις-κλειδιά
multiple-sclerosis patients, t-cell clones, angiotensin-ii, peptide analogs, rotating frame, lymphocyte-t, receptor, recognition, spectroscopy, h-1-nmr
Θεματική κατηγορία
Παραπομπή
Σύνδεσμος
<Go to ISI>://000079636000006
http://pubs.acs.org/doi/pdfplus/10.1021/jm980250e
http://pubs.acs.org/doi/pdfplus/10.1021/jm980250e
Γλώσσα
en
Εκδίδον τμήμα/τομέας
Όνομα επιβλέποντος
Εξεταστική επιτροπή
Γενική Περιγραφή / Σχόλια
Ίδρυμα και Σχολή/Τμήμα του υποβάλλοντος
Πανεπιστήμιο Ιωαννίνων. Σχολή Θετικών Επιστημών. Τμήμα Χημείας