title: High-Affinity α-Conotoxin PnIA Analogs Designed on the Basis of the Protein Surface Topography Method.
abstract: Despite some success for small molecules, elucidating structure-function relationships for biologically active peptides - the ligands for various targets in the organism - remains a great challenge and calls for the development of novel approaches. Some of us recently proposed the Protein Surface Topography (PST) approach, which benefits from a simplified representation of biomolecules' surface as projection maps, which enables the exposure of the structure-function dependencies. Here, we use PST to uncover the "activity pattern" in α-conotoxins - neuroactive peptides that effectively target nicotinic acetylcholine receptors (nAChRs). PST was applied in order to design several variants of the α-conotoxin PnIA, which were synthesized and thoroughly studied. Among the best was PnIA[R9, L10], which exhibits nanomolar affinity for the α7 nAChR, selectivity and a slow wash-out from this target. Importantly, these mutations could hardly be delineated by "standard" structure-based drug design. The proposed combination of PST with a set of experiments proved very efficient for the rational construction of new bioactive molecules.
authors.affiliation: Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 16/10 Miklukho-Maklaya Street, 117997 Moscow, Russia.
authors.forename: Igor E
authors.initials: IE
authors.lastname: Kasheverov
authors.affiliation: Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 16/10 Miklukho-Maklaya Street, 117997 Moscow, Russia.
authors.forename: Anton O
authors.initials: AO
authors.lastname: Chugunov
authors.affiliation: Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 16/10 Miklukho-Maklaya Street, 117997 Moscow, Russia.
authors.forename: Denis S
authors.initials: DS
authors.lastname: Kudryavtsev
authors.affiliation: Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 16/10 Miklukho-Maklaya Street, 117997 Moscow, Russia.
authors.forename: Igor A
authors.initials: IA
authors.lastname: Ivanov
authors.affiliation: Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 16/10 Miklukho-Maklaya Street, 117997 Moscow, Russia.
authors.forename: Maxim N
authors.initials: MN
authors.lastname: Zhmak
authors.affiliation: Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 16/10 Miklukho-Maklaya Street, 117997 Moscow, Russia.
authors.forename: Irina V
authors.initials: IV
authors.lastname: Shelukhina
authors.affiliation: Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 16/10 Miklukho-Maklaya Street, 117997 Moscow, Russia.
authors.forename: Ekaterina N
authors.initials: EN
authors.lastname: Spirova
authors.affiliation: Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 16/10 Miklukho-Maklaya Street, 117997 Moscow, Russia.|School of Biomedicine, Far Eastern Federal University, Bldg. M, 10, Ajax Village, Russky Island, Vladivostok 690000, Russia.|G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch, Russian Academy of Sciences, 159, Prospect 100 let Vladivostoku, 690022 Vladivostok, Russia.
authors.forename: Valentin M
authors.initials: VM
authors.lastname: Tabakmakher
authors.affiliation: G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch, Russian Academy of Sciences, 159, Prospect 100 let Vladivostoku, 690022 Vladivostok, Russia.
authors.forename: Elena A
authors.initials: EA
authors.lastname: Zelepuga
authors.affiliation: Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 16/10 Miklukho-Maklaya Street, 117997 Moscow, Russia.|National Research University Higher School of Economics, Myasnitskaya ul.20, 101000 Moscow, Russia.
authors.forename: Roman G
authors.initials: RG
authors.lastname: Efremov
authors.affiliation: Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 16/10 Miklukho-Maklaya Street, 117997 Moscow, Russia.
authors.forename: Victor I
authors.initials: VI
authors.lastname: Tsetlin
mesh_terms: D000495:Allosteric Site; D000818:Animals; D002942:Circular Dichroism; D003198:Computer Simulation; D020916:Conotoxins / Q000138:chemical synthesis* / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D056004:Molecular Dynamics Simulation; D009154:Mutation; D013329:Structure-Activity Relationship; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000378:metabolism*
chemical_list: D020916:Conotoxins; C089038:alpha-conotoxin PnIA; D064569:alpha7 Nicotinic Acetylcholine Receptor