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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

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Received: 1 August 2011; in revised form: 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 which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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MDPI and ACS Style

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.

AMA Style

Kasheverov IE, Zhmak MN, Khruschov AY, Tsetlin VI. Design of New α-Conotoxins: From Computer Modeling to Synthesis of Potent Cholinergic Compounds. Marine Drugs. 2011; 9(10):1698-1714.

Chicago/Turabian Style

Kasheverov, Igor E.; Zhmak, Maxim N.; Khruschov, Alexey Y.; Tsetlin, Victor I. 2011. "Design of New α-Conotoxins: From Computer Modeling to Synthesis of Potent Cholinergic Compounds." Mar. Drugs 9, no. 10: 1698-1714.


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