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 (Journal article)
Tselios, T./ Probert, L./ Daliani, I./ Matsoukas, E./ Troganis, A./ Gerothanassis, I. P./ Mavromoustakos, T./ Moore, G. J./ Matsoukas, J. M.
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.
|Institution and School/Department of submitter:||Πανεπιστήμιο Ιωαννίνων. Σχολή Θετικών Επιστημών. Τμήμα Χημείας|
|Keywords:||multiple-sclerosis patients,t-cell clones,angiotensin-ii,peptide analogs,rotating frame,lymphocyte-t,receptor,recognition,spectroscopy,h-1-nmr|
|Link:||<Go to ISI>://000079636000006|
|Publisher:||American Chemical Society|
|Appears in Collections:||Άρθρα σε επιστημονικά περιοδικά ( Ανοικτά)|
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