Cyclic Lactam Analogs Containing the Main Immunogenic Region of Torpedo Acetylcholine-Receptor (Journal article)

Detsikas, E./ Tsikaris, V./ Sakarellos-Daitsiotis, M./ Sakarellos, C./ Cung, M. T./ Marraud, M./ Vatzaki, E./ Tzartos, S. J.

The majority of autoantibodies against the nicotinic acetylcholine receptor (AChR) bind to an extracellular region of the AChR's alpha-subunit, named main immunogenic region (MIR), with the sequence W67-N-P-A-D-Y-G-G-I-K76 for the Torpedo californica electric organ. We report on the synthesis and the biological and H-1-NMR studies of two cyclic MIR compounds-namely, [D71,K76]-MIR-NH2 and Ac-[Orn68,D71,A76]-MIR-NH2. The relatively small chemical shift differences between [D71,K76]-MIR-NH2 and the biologically active [A76]-analogue suggest that both MIR derivatives possess similar conformations. Thus, the observed limited anti-MIR MAb binding capacity of [D71,K76]-MIR-NH2 is attributed to the D71,K76 side-chain blockage, through lactam. Formation of the Orn68,D71 cycle in the Ac-[Orn68,D71,A76]-MIR-NH2 preserves, unchanged, the low antigenicity of the linear Ac-[Orn68,A76]-MIR-NH2, thus confirming the key role of position 68. The low temperature coefficient value of A70-NH and the observed NOE effect between P69-C(delta)H2 and A70-NH in Ac-[Orn68, D71,A76]-MIR-NH2 argue in favor of a type I beta-turn in the Trp67-Orn-P-A70 sequence. However, the N-terminus beta-folding and the Orn68,D71 cycle appear ineffective for optimal antibody molecular recognition.
Institution and School/Department of submitter: Πανεπιστήμιο Ιωαννίνων. Σχολή Θετικών Επιστημών. Τμήμα Χημείας
Keywords: monoclonal-antibodies,activity profiles,alpha-subunit,side-chain,peptides,conformations,residues,cyclizations,localization,proteins
ISSN: 1040-5704
Link: <Go to ISI>://A1993KL67100004
Publisher: Eaton Publishing Co.
Appears in Collections:Άρθρα σε επιστημονικά περιοδικά ( Ανοικτά)

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