Cyclic Lactam Analogs Containing the Main Immunogenic Region of Torpedo Acetylcholine-Receptor
(EN)
Detsikas, E.
(EN)
Πανεπιστήμιο Ιωαννίνων. Σχολή Θετικών Επιστημών. Τμήμα Χημείας
(EL)
Detsikas, E.
(EN)
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.
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