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<article article-type="research-article" dtd-version="1.3" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xml:lang="ru"><front><journal-meta><journal-id journal-id-type="publisher-id">mimmun</journal-id><journal-title-group><journal-title xml:lang="ru">Медицинская иммунология</journal-title><trans-title-group xml:lang="en"><trans-title>Medical Immunology (Russia)</trans-title></trans-title-group></journal-title-group><issn pub-type="ppub">1563-0625</issn><issn pub-type="epub">2313-741X</issn><publisher><publisher-name>SPb RAACI</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="doi">10.15789/1563-0625-IOS-2486</article-id><article-id custom-type="elpub" pub-id-type="custom">mimmun-2486</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="section-heading" xml:lang="ru"><subject>ОРИГИНАЛЬНЫЕ СТАТЬИ</subject></subj-group><subj-group subj-group-type="section-heading" xml:lang="en"><subject>ORIGINAL ARTICLES</subject></subj-group></article-categories><title-group><article-title>Влияние мутационных вариантов спайкового гликопротеина и РНК-зависимой РНКполимеразы (nsp12) SARS-CoV-2 на участки стыковки с ремдесивиром</article-title><trans-title-group xml:lang="en"><trans-title>Influence of SARS-CoV-2 variants’ spike glycoprotein and RNA-dependent RNA polymerase (nsp12) mutations on remdesivir docking residues</trans-title></trans-title-group></title-group><contrib-group><contrib contrib-type="author" corresp="yes"><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0001-8988-5957</contrib-id><name-alternatives><name name-style="eastern" xml:lang="ru"><surname>Давуд</surname><given-names>Али А.</given-names></name><name name-style="western" xml:lang="en"><surname>Dawood</surname><given-names>Ali A.</given-names></name></name-alternatives><bio xml:lang="ru"><p>Автор: Али А. Давуд – кандидат микробиологических наук, лектор, кафедра анатомии.</p><p>1, г. Мосул. Тел.: 00964 (770)-176-8002</p></bio><bio xml:lang="en"><p>PhD (Microbiology), Lector, Department of Anatomy, College of Medicine.</p><p>st. 1, Mosul, Phone: 00964 (770)-176-8002</p></bio><email xlink:type="simple">aad@uomosul.edu.iq</email><xref ref-type="aff" rid="aff-1"/></contrib></contrib-group><aff-alternatives id="aff-1"><aff xml:lang="ru"><institution>Медицинский колледж, Мосульский университет</institution><country>Ирак</country></aff><aff xml:lang="en"><institution>University of Mosul</institution><country>Iraq</country></aff></aff-alternatives><pub-date pub-type="collection"><year>2022</year></pub-date><pub-date pub-type="epub"><day>13</day><month>07</month><year>2022</year></pub-date><volume>24</volume><issue>3</issue><fpage>617</fpage><lpage>628</lpage><permissions><copyright-statement>Copyright &amp;#x00A9; Давуд А.А., 2022</copyright-statement><copyright-year>2022</copyright-year><copyright-holder xml:lang="ru">Давуд А.А.</copyright-holder><copyright-holder xml:lang="en">Dawood A.A.</copyright-holder><license xml:lang="ru" license-type="creative-commons-attribution" xlink:href="https://creativecommons.org/licenses/by/4.0/" xlink:type="simple"><license-p>Данная работа распространяется под лицензией Creative Commons Attribution 4.0.</license-p></license><license xml:lang="en" license-type="creative-commons-attribution" xlink:href="https://creativecommons.org/licenses/by/4.0/" xlink:type="simple"><license-p>This work is licensed under a Creative Commons Attribution 4.0 License.</license-p></license></permissions><self-uri xlink:href="https://www.mimmun.ru/mimmun/article/view/2486">https://www.mimmun.ru/mimmun/article/view/2486</self-uri><abstract><p>В связи с быстрым развитием и эволюцией новых вариантов SARS-CoV-2 возникли проблемы, касающиеся их потенциального влияния на эффективность существующих вакцин. При этом наиболее значимые мутации касаются гена спайкового гликопротеина вируса. Ремдесивир, ингибирующий активность РНК-зависимой РНК-полимеразы (РдРп), является единственным препаратом, принятым FDA для лечения COVID-19 (nsp12). Исследовалось связывание (стыковка) гибкого лиганда (ремдесивира) с жесткими рецепторами (спайковый белок и РдРп). В ряде работ было обнаружено, что мутации спайкового гликопротеина и РдРп оказывают существенное влияние на поведение вируса и, в конечном счете, – на состояние здоровья человека. Показано, что позиция стыковки ремдесивира со спайковым белком и РдРп не определяется мутациями в недостающих петлях. Ремдесивир может связываться только с В- и С-цепями спайкового белка. Некоторые мутации могут передаваться в отдельных вариантах без изменения типа аминокислот, как, например, K417N, L452R, N501Y, D614G, T716I и S982A.</p></abstract><trans-abstract xml:lang="en"><p>Rapid emergence and evolution of novel SARS-CoV-2 variants has raised concerns about their potential impact on efficiency of currently available vaccines. Among the most significant target mutations in the virus are those of the spike glycoprotein. Remdesivir, which inhibits the polymerase activity of the RNAdependent RNA polymerase RdRp, is the only medicine approved by FDA for treatment of COVID-19 (nsp12). The docking features of the flexible ligand (remdesivir) with the stiff receptors was investigated in the present study (S protein and RdRp interaction). In various studies, the spike glycoprotein and RdRp mutations were found to have a significant influence upon viral behaviour and, as a result, affect human health. The docking position of remdesivir with the S and RdRp proteins was shown to be unaffected by mutations in the missing loops. The remdesivir can only bind the B and C chains of S protein. Some mutations can be transferred between variations, without changing the type of amino acid, such as K417N, L452R, N501Y, D614G, T716I, and S982A.</p></trans-abstract><kwd-group xml:lang="ru"><kwd>COVID-19</kwd><kwd>ремдесивир</kwd><kwd>РНК-зависимая РНК-полимераза</kwd><kwd>спайковый белок</kwd><kwd>мутации</kwd></kwd-group><kwd-group xml:lang="en"><kwd>COVID-19</kwd><kwd>remdesivir</kwd><kwd>RdRp</kwd><kwd>S protein</kwd><kwd>mutation</kwd></kwd-group></article-meta></front><back><ref-list><title>References</title><ref id="cit1"><label>1</label><citation-alternatives><mixed-citation xml:lang="ru">Baum A., Fulton B.O., Wloga E., Copin R., Pascal K.E., Russo V., Giordano S., Lanza K., Negron N., Ni M., Wei Y., Atwal G.S., Murphy A.J., Stahl N., Yancopoulos G.D., Kyratsous C.A. Antibody cocktail to SARSCoV-2 spike protein prevents rapid mutational escape seen with individual antibodies. Science, 2020, Vol. 369, pp. 1014-1018.</mixed-citation><mixed-citation xml:lang="en">Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. 2020; 382: 727–733. doi.org/10.1056/NEJMoa2001017.</mixed-citation></citation-alternatives></ref><ref id="cit2"><label>2</label><citation-alternatives><mixed-citation xml:lang="ru">Choy K.-T., Wong A.Y.-L., Kaewpreedee P., Sia S.F., Chen D., Hui K.P.Y., Chu D.K.W., Chan M.C.W., Cheung P.P.-H., Huang X., Peiris M., Yen H.-L. Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARSCoV-2 replication in vitro. Antiviral Res., 2020, Vol. 178, 104786. doi: 10.1016/j.antiviral.2020.104786.</mixed-citation><mixed-citation xml:lang="en">Salleh MZ, Derrick JP, Deris ZZ. Structural Evaluation of the Spike Glycoprotein Variants on SARS-CoV-2 Transmission and Immune Evasion. Inter J Mole Sci. 2021; 22(14):7425. doi.org/10.3390/ijms22147425.</mixed-citation></citation-alternatives></ref><ref id="cit3"><label>3</label><citation-alternatives><mixed-citation xml:lang="ru">Dawood A., Altobje M., Alnori H. Compatibility of the ligand binding sites in the spike glycoprotein of covid-19 with those in the aminopeptidase and the caveolins 1, 2 proteins. Res. J. Pharm. Tech., 2021, Vol. 14, no. 9, pp. 4760-4766.</mixed-citation><mixed-citation xml:lang="en">Wu  C,  Chen  X,  Cai  Y,  Xia  J,  Zhou  X.  Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med. 2019.</mixed-citation></citation-alternatives></ref><ref id="cit4"><label>4</label><citation-alternatives><mixed-citation xml:lang="ru">Dawood A., Altobje M., Alrassam Z. Molecular docking of SARS-CoV-2 nucleocapsid protein with angiotensin-converting enzyme II. Mikrobiol. Zhu, 2021, Vol. 83, no. 2, pp. 82-92.</mixed-citation><mixed-citation xml:lang="en">Shaeen A, Sattar N, Ibrahim M, and Irfan M. Role of Remdesivir in COVID-19. Aus J Pulm Res Med. 2021; 8(1):1071.</mixed-citation></citation-alternatives></ref><ref id="cit5"><label>5</label><citation-alternatives><mixed-citation xml:lang="ru">Dawood A., Altobje M. Inhibition of N-linked glycosylation by nunicamycin may contribute to the treatment of SARS-CoV-2. Microbiol. Path., 2020, Vol. 149, 104586. doi: 10.1016/j.micpath.2020.104586.</mixed-citation><mixed-citation xml:lang="en">Shehroz M, Zaheer T, and Hussain T. Computer-aided drug design against spike glycoprotein of SARS-CoV-2 to aid COVID-19 treatment. Heliyon. 2020; e05278. doi.org/10.1016/j.heliyon.2020.e05278.</mixed-citation></citation-alternatives></ref><ref id="cit6"><label>6</label><citation-alternatives><mixed-citation xml:lang="ru">Dawood A. Glycosylation, ligand binding sites and antigenic variations between membrane glycoprotein of COVID-19 and related coronaviruses. Vacunas. 2021, Vol. 22, no. 1, pp. 1-9.</mixed-citation><mixed-citation xml:lang="en">Dawood A, Altobje M, and Alnori H. Compatibility of the Ligand Binding Sites in the Spike Glycoprotein of COVID-19 with those in the Aminopeptidase and the Caveolins 1, 2 Proteins. Res J Pharm Tech. 2021; 14(9): 4760-4766. Doi.org/10.52711/0974-360X.2021.00828.</mixed-citation></citation-alternatives></ref><ref id="cit7"><label>7</label><citation-alternatives><mixed-citation xml:lang="ru">Dawood A. Identification of CTL and B-cell epitopes in the Nucleocapsid Phosphoprotein of COVID-19 using Immunoinformatics. Microbiol. J., 2021, Vol. 83, no. 1, pp. 78-86.</mixed-citation><mixed-citation xml:lang="en">Baum, A. et al. Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies. Science. 2020; 369, 1014–1018.</mixed-citation></citation-alternatives></ref><ref id="cit8"><label>8</label><citation-alternatives><mixed-citation xml:lang="ru">Dawood A. New variant of SARS-CoV-2 in South Africa. Prog. Med. Sc., 2021, Vol. 5, no. 1, pp. 1-2.</mixed-citation><mixed-citation xml:lang="en">Senger MR, Evangelista TCS, Dantas RF, Santana MVDS, Gonçalves LCS, de Souza Neto LR, et al. COVID-19: molecular targets, drug repurposing and new avenues for drug discovery. Mem Inst Oswaldo Cruz. 2020; Oct 2; 115:e200254. doi: 10.1590/0074-02760200254. PMID: 33027420; PMCID: PMC7534958.</mixed-citation></citation-alternatives></ref><ref id="cit9"><label>9</label><citation-alternatives><mixed-citation xml:lang="ru">Dawood A. Using remdesivir and dexamethasone for treatment of SARS-CoV-2 shortens the patient’s stay in the hospital. Asi an J. Pharm. Res., 2021, Vol. 11, Iss. 2, 138-0. doi: 10.52711/2231-5691.2021.00026.</mixed-citation><mixed-citation xml:lang="en">Wang M, Cao R, Zhang L, Yang X, Liu J.  Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020; 30: 269-271.</mixed-citation></citation-alternatives></ref><ref id="cit10"><label>10</label><citation-alternatives><mixed-citation xml:lang="ru">Deshpande R., Tiwari P., Nyayanit N., Modak M. In silico molecular docking analysis for repurposing therapeutics against multiple proteins from SARS-CoV-2. Eur. J. Pharmacol., 2020, Vol. 886, 173430. doi.org/10.1016/j.ejphar.2020.173430.</mixed-citation><mixed-citation xml:lang="en">Hall Jr, and Ji H-F. A search for medications to treat COVID-19 via in silico molecular docking models of the SARS-CoV-2 spike glycoprotein and 3CL protease. Travel Med Infect Dis. 2020; 35:101646. doi .org/0.1016/j.tmaid.2020.101646.</mixed-citation></citation-alternatives></ref><ref id="cit11"><label>11</label><citation-alternatives><mixed-citation xml:lang="ru">Eskier D., Karakülah G., Suner A., Oktay Y. RdRp mutations are associated with SARS-CoV-2 genome evolution. Peer J., 2020, Vol. 8, e9587. doi:/10.7717/peerj.9587.</mixed-citation><mixed-citation xml:lang="en">Choy T, Wong Y, Kaewpreedee P, Sia F, Chen D, Hui   Y, et al. Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARSCoV-2 replication in vitro. Antiviral Res. 2020; 178:104786. Doi.org/10.1016/j.antiviral.2020.104786.</mixed-citation></citation-alternatives></ref><ref id="cit12"><label>12</label><citation-alternatives><mixed-citation xml:lang="ru">Eweas A., Alhossary A., Abdul-Moneim A. Molecular Docking Reveals ivermectin and remdesivir as potential repurposed drugs against SARS-CoV-2. Front. Microbiol., 2021, Vol. 11, e592908. doi: 10.3389/fmicb.2020.592908.</mixed-citation><mixed-citation xml:lang="en">Grein J, Ohmagari N, Shin D, Diaz G, Asperges E. Compassionate use of remdesivir for patients with severe Covid-19. N Engl J Med. 2020; 382: 2327-2336.</mixed-citation></citation-alternatives></ref><ref id="cit13"><label>13</label><citation-alternatives><mixed-citation xml:lang="ru">Garvin M.R., Prates E.T., Pavicic M., Jones P., Amos B.K., Geiger A., Shah M.B., Streich J., Gazolla J.G.F.M., Kainer D., Cliff A., Romero J., Keith N., Brown J.B., Jacobson D. Potentially adaptive SARS-CoV-2 mutations discovered with novel spatiotemporal and explainable AI models. Genome Biol., 2020, Vol. 21, 304. doi: 10.1186/s13059-020-02191-0.</mixed-citation><mixed-citation xml:lang="en">Dawood A. Using Remdesivir and Dexamethasone for Treatment of SARS-CoV-2 Shortens the patient's stay in the Hospital. Asi J Pharm Res. 2021; 11(2):138-0. doi.org/10.52711/2231-5691.2021.00026.</mixed-citation></citation-alternatives></ref><ref id="cit14"><label>14</label><citation-alternatives><mixed-citation xml:lang="ru">Grein J., Ohmagari N., Shin D., Diaz G., Asperges E. Compassionate use of remdesivir for patients with severe Covid-19. N. Engl. J. Med., 2020, Vol. 382, pp. 2327-2336.</mixed-citation><mixed-citation xml:lang="en">Yin W, Mao C, Luan X, Shen D-D, Shen Q, Su H., et al. Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir. Science.2020; 368: 1499–1504. doi.org/10.1126/science.abc1560.</mixed-citation></citation-alternatives></ref><ref id="cit15"><label>15</label><citation-alternatives><mixed-citation xml:lang="ru">Hall Jr., Ji H-F. A search for medications to treat COVID-19 via in silico molecular docking models of the SARS-CoV-2 spike glycoprotein and 3CL protease. Travel Med. Infect. Dis., 2020, Vol. 35, 101646. doi: 0.1016/j.tmaid.2020.101646.</mixed-citation><mixed-citation xml:lang="en">Eweas A, Alhossary A, and Abdul-Moneim A. Molecular Docking Reveals Ivermectin and Remdesivir as Potential Repurposed Drugs against SARS-CoV-2. Front Micro. 2021; 11:e 592908. doi.org/10.3389/fmicb.2020.592908.</mixed-citation></citation-alternatives></ref><ref id="cit16"><label>16</label><citation-alternatives><mixed-citation xml:lang="ru">Henderson R., Edwards R.J., Mansouri K., Janowska K., Stalls V., Gobeil S.M.C., Kopp M., Li D., Parks R., Hsu A.L., Borgnia M.J., Haynes B.F., Priyamvada acharya controlling the SARS-CoV-2 spike glycoprotein conformation. Nat. Struct. Mol. Biol., 2020, Vol. 27, pp. 925-933.</mixed-citation><mixed-citation xml:lang="en">Sada, M. et al. Detailed Molecular Interactions of Favipiravir with SARS-CoV-2, SARS-CoV, MERS-CoV, and Influenza Virus Polymerases In Silico. Microorganisms.2020: 8, 1610.</mixed-citation></citation-alternatives></ref><ref id="cit17"><label>17</label><citation-alternatives><mixed-citation xml:lang="ru">Ilmjärv S., Abdul F., Acosta-Gutiérrez S., Estarellas C., Galdadas I., Casimir M., Alessandrini M., Gervasio F.L., Krause K.-H. Concurrent mutations in RNA-dependent RNA polymerase and spike protein emerged as the epidemiologically most successful SARS-CoV-2 variant. Sci. Rep., 2021, Vol. 11, 13705. doi: 10.1038/s41598021-91662-w.</mixed-citation><mixed-citation xml:lang="en">Hall Jr, and Ji H.-F. A search for medications to treat COVID-19 via in silico molecular docking models of the SARS-CoV-2 spike glycoprotein and 3CL protease. Travel Med Infect Dis. 2020; 35:101646. Doi.org/10.1016/j.tmaid.2020.101646.</mixed-citation></citation-alternatives></ref><ref id="cit18"><label>18</label><citation-alternatives><mixed-citation xml:lang="ru">Jean S., Lee I., Hsueh R. Treatment options for COVID-19: the reality and challenges. J. Microbiol. Immunol. Infect., 2020, Vol. 53, pp. 436-443.</mixed-citation><mixed-citation xml:lang="en">Dawood A, Altobje M, and Alrassam Z. Molecular Docking of SARS-CoV-2 Nucleocapsid Protein with Angiotensin-Converting Enzyme II. Mikrobio Zhu. 2021; 83(2):82-92. Doi.org/10.15407/microbiolj83.02.082.</mixed-citation></citation-alternatives></ref><ref id="cit19"><label>19</label><citation-alternatives><mixed-citation xml:lang="ru">Kumar Y., Singh H., Patel C.N. In silico prediction of potential inhibitors for the main protease of SARSCoV-2 using molecular docking and dynamics simulation based drug-repurposing. J. Infect. Public Health, 2020, Vol. 13, pp. 1210-1223.</mixed-citation><mixed-citation xml:lang="en">Sun C, Zhang J, Wei J, Zheng X, Zhao X, and Fang Z, et al. Screening, simulation, and optimization design of small molecule inhibitors of the SARS-CoV-2 spike glycoprotein. PLOS One. 2021; Jan: 1-21.  doi.org/10.1371/journal.pone.0245975.</mixed-citation></citation-alternatives></ref><ref id="cit20"><label>20</label><citation-alternatives><mixed-citation xml:lang="ru">Mari A., Roloff T., Stange M., Søgaard K.K., Asllanaj E., Tauriello G., Alexander L.T., Schweitzer M., Leuzinger K., Gensch A., Martinez A.E., Bielicki J., Pargger H., Siegemund M., Nickel C.H., Bingisser R., Osthoff M., Bassetti S., Sendi P., Battegay M., Marzolini C., Seth-Smith H.M.B., Schwede T., Hirsch H.H., Egli A. Global genomic analysis of SARS-CoV-2 RNA dependent RNA polymerase evolution and antiviral drug resistance. Microorganisms, 2021, Vol. 9, no. 5, 1094. doi: 10.3390/microorganisms9051094.</mixed-citation><mixed-citation xml:lang="en">Zhang, Q., Xiang, R., Huo, S. et al. Molecular mechanism of interaction between SARS-CoV-2 and host cells and interventional therapy. Sig Transduct Target Ther. 2021; 6(233) doi.org/10.1038/s41392-021-00653-w.</mixed-citation></citation-alternatives></ref><ref id="cit21"><label>21</label><citation-alternatives><mixed-citation xml:lang="ru">Nguyen H., Thai N., Truong D., Li M. Remdesivir Strongly Binds to Both RNA-Dependent RNA polymerase and Main Protease of SARS-CoV-2: Evidence from Molecular Simulations. J. Phys. Chem., 2020, Vol. 124, pp. 11337-11348.</mixed-citation><mixed-citation xml:lang="en">Dawood A. Glycosylation,  ligand  binding  sites  and  antigenic variations  between  membrane  glycoprotein  of COVID-19  and  related  coronaviruses. Vacunas. 2021; 22(1): 1-9. Doi.org/10.1016/j.vacun.2020.09.005.</mixed-citation></citation-alternatives></ref><ref id="cit22"><label>22</label><citation-alternatives><mixed-citation xml:lang="ru">Pachetti M., Marini B., Benedetti F., Giudici F., Mauro E., Storici P., Masciovecchio C., Angeletti S., Ciccozzi M., Gallo R.C., Zella D., Ippodrino R. Emerging SARS-CoV-2 mutation hot spots include a novel RNAdependent-RNA polymerase variant. J. Transl. Med., 2020, Vol. 18, no. 1, 179. doi.org/10.1186/s12967-020-02344-6.</mixed-citation><mixed-citation xml:lang="en">Dawood A. New Variant of SARS-CoV-2 in South Africa. Prog Med Sc. 2021; 5(1): 1-2. doi.org/10.5455/pms.20211013.</mixed-citation></citation-alternatives></ref><ref id="cit23"><label>23</label><citation-alternatives><mixed-citation xml:lang="ru">Sada M., Saraya T., Ishii H., Okayama K., Hayashi Y., Tsugawa T., Nishina A., Murakami K., Kuroda M., Ryo A., Kimura H. Detailed molecular interactions of favipiravir with SARS-CoV-2, SARS-CoV, MERS-CoV, and influenza virus polymerases in silico. Microorganisms, 2020, Vol. 8, no. 10, 1610. doi: 10.3390/microorganisms8101610.</mixed-citation><mixed-citation xml:lang="en">Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020; 30:269–271. doi.org/10.1038/s41422-020-0282-0.</mixed-citation></citation-alternatives></ref><ref id="cit24"><label>24</label><citation-alternatives><mixed-citation xml:lang="ru">Salleh M.Z., Derrick J.P., Deris Z.Z. Structural evaluation of the spike glycoprotein variants on SARS-CoV-2 transmission and immune evasion. Inter. J. Mol. Sci., 2021, Vol. 22, no. 14, 7425. doi.org/10.3390/ijms22147425.</mixed-citation><mixed-citation xml:lang="en">Showers W, Leach S, Kechris K, and Strong M. Analysis of SARS-CoV-2 Mutations over Time Reveals Increasing Prevalence of Variants in the Spike Protein and RNA-Dependent RNA polymerase. bioRxiv. 2021. doi:/10.1101/2021.03.05.433666.</mixed-citation></citation-alternatives></ref><ref id="cit25"><label>25</label><citation-alternatives><mixed-citation xml:lang="ru">Senger M.R., Evangelista T.C.S., Dantas R.F., Santana M.V.D.S., Gonçalves L.C.S., de Souza Neto L.R., Ferreira S.B., Silva-Junior F.P. COVID-19: molecular targets, drug repurposing and new avenues for drug discovery. Mem. Inst. Oswaldo Cruz, 2020, Vol. 115, e200254. doi: 10.1590/0074-02760200254.</mixed-citation><mixed-citation xml:lang="en">Garvin R, Prates E, Pavicic M, et al. Potentially adaptive SARS-CoV-2 mutations discovered with novel spatiotemporal and explainable AI models. Genome Biol. 2020; 21 (304). doi.org/10.1186/s13059-020-02191-0.</mixed-citation></citation-alternatives></ref><ref id="cit26"><label>26</label><citation-alternatives><mixed-citation xml:lang="ru">Shaeen A., Sattar N., Ibrahim M., Irfan M. Role of Remdesivir in COVID-19. Aus. J. Pulm. Res. Med., 2021, Vol. 8, no. 1, 1071.</mixed-citation><mixed-citation xml:lang="en">Dawood A. Identification of CTL and B-cell epitopes in the Nucleocapsid Phosphoprotein of COVID-19 using Immunoinformatics. Microbiol J. 2021; 83(1): 78-86. doi.org/10.15407/microbiolj83.01.078.</mixed-citation></citation-alternatives></ref><ref id="cit27"><label>27</label><citation-alternatives><mixed-citation xml:lang="ru">Sheahan T.P., Sims A.C., Leist S.R., Schafer A., Won J. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat. Commun., 2020, Vol. 11, no. 1, 222. doi: 10.1038/s41467-019-13940-6.</mixed-citation><mixed-citation xml:lang="en">Mari A, Roloff T, Stange M, Søgaard K, Asllanaj E, Tauriello G, et al. Global Genomic Analysis of SARS-CoV-2 RNA Dependent RNA Polymerase Evolution and Antiviral Drug Resistance. Microorganisms. 2021; 9(5):1094. doi.org/10.3390/microorganisms9051094.</mixed-citation></citation-alternatives></ref><ref id="cit28"><label>28</label><citation-alternatives><mixed-citation xml:lang="ru">Shehroz M., Zaheer T., Hussain T. Computer-aided drug design against spike glycoprotein of SARS-CoV-2 to aid COVID-19 treatment. Heliyon, 2020, Vol. 6, no. 10, e05278. doi.org/10.1016/j.heliyon.2020.e05278.</mixed-citation><mixed-citation xml:lang="en">Dawood A, Altobje M. Inhibition of N-linked Glycosylation by Tunicamycin May Contribute to The Treatment of SARS-CoV-2. Microbiol Path. 2020; 149:104586. doi.org/10.1016/j.micpath.2020.104586.</mixed-citation></citation-alternatives></ref><ref id="cit29"><label>29</label><citation-alternatives><mixed-citation xml:lang="ru">Showers W., Leach S., Kechris K., Strong M. Analysis of SARS-CoV-2 Mutations over time reveals increasing prevalence of variants in the spike protein and RNA-dependent RNA polymerase. bioRxiv, 2021. doi: 10.1101/2021.03.05.433666.</mixed-citation><mixed-citation xml:lang="en">Nguyen H, Thai N, Truong D, and Li M. Remdesivir Strongly Binds to Both RNA-Dependent RNA polymerase and Main Protease of SARS-CoV-2: Evidence from Molecular Simulations. J Phys Chem. 2020; 124, 11337−11348. doi.org/10.1021/acs.jpcb.0c07312.</mixed-citation></citation-alternatives></ref><ref id="cit30"><label>30</label><citation-alternatives><mixed-citation xml:lang="ru">Sun C., Zhang J., Wei J., Zheng X., Zhao X., Fang Z., Xu D., Yuan H., Liu Y. Screening, simulation, and optimization design of small molecule inhibitors of the SARS-CoV-2 spike glycoprotein. PLoS One, 2021, Vol. 16, no. 1, e0245975. doi: 10.1371/journal.pone.0245975.</mixed-citation><mixed-citation xml:lang="en">Kumar, Y., Singh, H., and Patel, C. N. In silico prediction of potential inhibitors for the main protease of SARS-CoV-2 using molecular docking and dynamics simulation based drug-repurposing. J Infect Pub Heal. 2020; 13: 1210–1223. doi.org/10.1016/j.jiph.2020.06.016.</mixed-citation></citation-alternatives></ref><ref id="cit31"><label>31</label><citation-alternatives><mixed-citation xml:lang="ru">Walls C., Park Y.-J., Tortorici A., Wall A., Mcguire T., Veesler D. Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell, 2020, Vol. 181, pp. 281.e6-292.e6.</mixed-citation><mixed-citation xml:lang="en">Williamson B, Feldmann F, Schwarz B, Meade-White K, Porter D. Clinical benefit of remdesivir in rhesus macaques infected with COVID-19. 2020.</mixed-citation></citation-alternatives></ref><ref id="cit32"><label>32</label><citation-alternatives><mixed-citation xml:lang="ru">Wang M., Cao R., Zhang L., Yang X., Liu J., Xu M., Shi Z., Hu Z., Zhong W., Xiao G. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res., 2020, Vol. 30, pp. 269-271.</mixed-citation><mixed-citation xml:lang="en">Sheahan TP, Sims AC, Leist SR, Schafer A, Won J. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat Commun. 2020; 11: 222.</mixed-citation></citation-alternatives></ref><ref id="cit33"><label>33</label><citation-alternatives><mixed-citation xml:lang="ru">Williamson B.N., Feldmann F., Schwarz B., Meade-White K., Porter D.P., Schulz J., van Doremalen N., Leighton I., Yinda C.K., Pérez-Pérez L., Okumura A., Lovaglio J., Hanley P.W., Saturday G., Bosio C.M., Anzick S., Barbian K., Cihlar T., Martens C., Scott D.P., Munster V.J., de Wit E. Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-19. Nature, 2020, Vol. 585, pp. 273-276.</mixed-citation><mixed-citation xml:lang="en">Yin, W. et al. Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir. Science. 2020; 368, 1499–1504.</mixed-citation></citation-alternatives></ref><ref id="cit34"><label>34</label><citation-alternatives><mixed-citation xml:lang="ru">Wu A., Peng Y., Huang B., Ding X., Wang X., Niu P., Meng J., Zhu Z., Zhang Z., Wang J., Sheng J., Quan L., Xia Z., Tan W., Cheng G., Jiang T. Genome composition and divergence of the novel coronavirus (2019-nCoV) originating in China. Cell Host Microbe, 2020, Vol. 27, pp. 325-328.</mixed-citation><mixed-citation xml:lang="en">Yurkovetskiy, L. et al. Structural and Functional Analysis of the D614G SARS-CoV-2 Spike Protein Variant. Cell. 2020; 183: 739-751.e8.</mixed-citation></citation-alternatives></ref><ref id="cit35"><label>35</label><citation-alternatives><mixed-citation xml:lang="ru">Wu C., Chen X., Cai Y., Xia J., Zhou X. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern. Med., 2020, Vol. 180, no. 7, pp. 1-11.</mixed-citation><mixed-citation xml:lang="en">Sheahan  P, Sims C, Leist  R, Schäfer A, Won J, Brown J, et al. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat. Commun. 2020; 11:222. doi.org/ 10.1038/s41467-019-13940-6.</mixed-citation></citation-alternatives></ref><ref id="cit36"><label>36</label><citation-alternatives><mixed-citation xml:lang="ru">Yin W., Mao C., Luan X., Shen D.-D., Shen Q., Su H., Wang X., Zhou F., Zhao W., Gao M., Chang S., Xie Y.C., Tian G., Jiang H.-W., Tao S.-C., Shen J., Jiang Y., Jiang H., Xu Y., Zhang S., Zhang Y., Xu H.E. Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir. Science, 2020, Vol. 368, pp. 1499-1504.</mixed-citation><mixed-citation xml:lang="en">Pachetti M, Marini B, Benedetti F. et al. Emerging SARS-CoV-2 mutation hot spots include a novel RNA-dependent-RNA polymerase variant. J Transl Med. 2020; 18 (179). doi.org/10.1186/s12967-020-02344-6.</mixed-citation></citation-alternatives></ref><ref id="cit37"><label>37</label><citation-alternatives><mixed-citation xml:lang="ru">Yurkovetskiy L. Wang X., Pascal K.E., Tomkins-Tinch C., Nyalile T.P., Wang Y., Baum A., Diehl W.E., Dauphin A., Carbone C., Veinotte K., Egri S.B., Schaffner S.F., Lemieux J.E., Munro J.B., Rafique A., Barve A., Sabeti P.C., Kyratsous C.A., Dudkina N.V., Shen K., Luban J. Structural and functional analysis of the D614G SARSCoV-2 spike protein variant. Cell, 2020, Vol. 183, pp. 739-751.e8.</mixed-citation><mixed-citation xml:lang="en">Walls C, Park Y.-J, Tortorici A, Wall A, Mcguire T, and Veesler D. Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell. 2020; 181: 281.e6–292.e6. doi.org/10.1016/j.cell.2020.11.032.</mixed-citation></citation-alternatives></ref><ref id="cit38"><label>38</label><citation-alternatives><mixed-citation xml:lang="ru">Zhang Q., Xiang R., Huo S., Zhou Y., Jiang S., Wang Q., Yu F. Molecular mechanism of interaction between SARS-CoV-2 and host cells and interventional therapy. Sig. Transduct. Target. Ther., 2021, Vol. 6, no. 1, 233. doi: 10.1038/s41392-021-00653-w.</mixed-citation><mixed-citation xml:lang="en">Wu A, Peng Y, Huang B, Ding X, Wang X, Niu P, et al. Genome composition and divergence of the novel coronavirus (2019-nCoV) originating in China. Cell Host Microbe. 2020; 27, 325–328.</mixed-citation></citation-alternatives></ref><ref id="cit39"><label>39</label><citation-alternatives><mixed-citation xml:lang="ru">Zhu N., Zhang D., Wang W., Li X., Yang B., Song J., Zhao X., Huang B., Shi W., Lu R., Niu P., Zhan F., Ma X., Wang D., Xu W., Wu G., Gao G.F., Tan W. A novel coronavirus from patients with pneumonia in China, 2019. N. Engl. J. Med., 2020, Vol. 382, pp. 727-733.</mixed-citation><mixed-citation xml:lang="en">Ilmjärv S, Abdul F, Acosta-Gutiérrez S. et al. Concurrent mutations in RNA-dependent RNA polymerase and spike protein emerged as the epidemiologically most successful SARS-CoV-2 variant. Sci Rep. 2021; 11 (13705). doi.org/10.1038/s41598-021-91662-w.</mixed-citation></citation-alternatives></ref><ref id="cit40"><label>40</label><citation-alternatives><mixed-citation xml:lang="ru">Eskier D, Karakülah G, Suner A, Oktay Y. RdRp mutations are associated with SARS-CoV-2 genome evolution. Peer J. 2020; Jul 21; 8:e9587. doi:/10.7717/peerj.9587. PMID: 32742818.  PMCID: PMC7380272.</mixed-citation><mixed-citation xml:lang="en">Eskier D, Karakülah G, Suner A, Oktay Y. RdRp mutations are associated with SARS-CoV-2 genome evolution. Peer J. 2020; Jul 21; 8:e9587. doi:/10.7717/peerj.9587. PMID: 32742818.  PMCID: PMC7380272.</mixed-citation></citation-alternatives></ref><ref id="cit41"><label>41</label><citation-alternatives><mixed-citation xml:lang="ru">Deshpande R, Tiwari P, Nyayanit N, and Modak M. In silico molecular docking analysis for repurposing therapeutics against multiple proteins from SARS-CoV-2. Eur J Pharmacol. 2020; 886:173430. doi.org/10.1016/j.ejphar.2020.173430.</mixed-citation><mixed-citation xml:lang="en">Deshpande R, Tiwari P, Nyayanit N, and Modak M. In silico molecular docking analysis for repurposing therapeutics against multiple proteins from SARS-CoV-2. Eur J Pharmacol. 2020; 886:173430. doi.org/10.1016/j.ejphar.2020.173430.</mixed-citation></citation-alternatives></ref><ref id="cit42"><label>42</label><citation-alternatives><mixed-citation xml:lang="ru">Jean S, Lee I, and Hsueh R. Treatment options for COVID-19: the reality and challenges. J Microbiol Immunol Infect. 2020; 53: 436–443.</mixed-citation><mixed-citation xml:lang="en">Jean S, Lee I, and Hsueh R. Treatment options for COVID-19: the reality and challenges. J Microbiol Immunol Infect. 2020; 53: 436–443.</mixed-citation></citation-alternatives></ref><ref id="cit43"><label>43</label><citation-alternatives><mixed-citation xml:lang="ru">Henderson R. et al. Controlling the SARS-CoV-2 spike glycoprotein conformation. Nat Struct Mol Biol. 2020; 27: 925–933.</mixed-citation><mixed-citation xml:lang="en">Henderson R. et al. Controlling the SARS-CoV-2 spike glycoprotein conformation. Nat Struct Mol Biol. 2020; 27: 925–933.</mixed-citation></citation-alternatives></ref></ref-list><fn-group><fn fn-type="conflict"><p>The authors declare that there are no conflicts of interest present.</p></fn></fn-group></back></article>
