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Mar. Drugs 2011, 9(10), 1698-1714; doi:10.3390/md9101698
Article

Design of New α-Conotoxins: From Computer Modeling to Synthesis of Potent Cholinergic Compounds

* ,
,
 and
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya Street, 16/10 Moscow 117997, Russia
* Author to whom correspondence should be addressed.
Received: 1 August 2011 / Revised: 29 August 2011 / Accepted: 16 September 2011 / Published: 28 September 2011
(This article belongs to the Special Issue Conotoxins)
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Abstract

A series of 14 new analogs of α-conotoxin PnIA Conus pennaceus was synthesized and tested for binding to the human α7 nicotinic acetylcholine receptor (nAChR) and acetylcholine-binding proteins (AChBP) Lymnaea stagnalis and Aplysia californica. Based on computer modeling and the X-ray structure of the A. californica AChBP complex with the PnIA[A10L, D14K] analog [1], single and multiple amino acid substitutions were introduced in α-conotoxin PnIA aimed at compounds of higher affinity and selectivity. Three analogs, PnIA[L5H], PnIA[A10L, D14K] and PnIA[L5R, A10L, D14R], have high affinities for AChBPs or α7 nAChR, as found in competition with radioiodinated α-bungarotoxin. That is why we prepared radioiodinated derivatives of these α-conotoxins, demonstrated their specific binding and found that among the tested synthetic analogs, most had almost 10-fold higher affinity in competition with radioactive α-conotoxins as compared to competition with radioactive α-bungarotoxin. Thus, radioiodinated α-conotoxins are a more sensitive tool for checking the activity of novel α-conotoxins and other compounds quickly dissociating from the receptor complexes.
Keywords: α-conotoxin analogs; nicotinic acetylcholine receptors; acetylcholine-binding proteins; computer modeling; radioligand analysis α-conotoxin analogs; nicotinic acetylcholine receptors; acetylcholine-binding proteins; computer modeling; radioligand analysis
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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Kasheverov, I.E.; Zhmak, M.N.; Khruschov, A.Y.; Tsetlin, V.I. Design of New α-Conotoxins: From Computer Modeling to Synthesis of Potent Cholinergic Compounds. Mar. Drugs 2011, 9, 1698-1714.

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