title: Design of new α-conotoxins: from computer modeling to synthesis of potent cholinergic compounds.
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, 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.
authors.affiliation: Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya Street, 16/10 Moscow 117997, Russia.
authors.forename: Igor E
authors.initials: IE
authors.lastname: Kasheverov
authors.affiliation: Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya Street, 16/10 Moscow 117997, Russia.
authors.forename: Maxim N
authors.initials: MN
authors.lastname: Zhmak
authors.affiliation: Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya Street, 16/10 Moscow 117997, Russia.
authors.forename: Alexey Y
authors.initials: AY
authors.lastname: Khruschov
authors.affiliation: Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya Street, 16/10 Moscow 117997, Russia.
authors.forename: Victor I
authors.initials: VI
authors.lastname: Tsetlin
mesh_terms: D000818:Animals; D001048:Aplysia / Q000378:metabolism; D001667:Binding, Competitive; D002038:Bungarotoxins / Q000378:metabolism; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism; D017076:Computer-Aided Design; D020916:Conotoxins / Q000138:chemical synthesis / Q000737:chemistry*; D015195:Drug Design; D054879:Halogenation; D006801:Humans; D008195:Lymnaea / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011869:Radioligand Assay; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C428944:AChBP protein, Lymnaea; D002038:Bungarotoxins; D002352:Carrier Proteins; C579167:Chrna7 protein, human; D020916:Conotoxins; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor
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