项目来源

俄罗斯科学基金(RSF)

项目主持人

Shetnev Anton

项目受资助机构

Yaroslavl State Pedagogical University named after K.D.Ushinsky

项目编号

22-23-20158

立项年度

2022

立项时间

未公开

项目级别

国家级

研究期限

未知 / 未知

受资助金额

未知

学科

CHEMISTRY AND MATERIAL SCIENCES-medical chemistry and prediction of various types of biological activity;Synthesis,structure,and properties of natural and physiologically active substances

学科代码

03-03-103

基金类别

未公开

Сульфонамид ; мишень-ориентированный синтез ; энтеровирусы ; капсид ; межпротомерный VP1-VP3 карман ; ингибитор ; скрининг ; Sulfonamid ; targed-based synthesis ; Enterovirus ; capsid ; interprotomer VP1-VP3 pocket ; inhibitor ; screening

参与者

未公开

参与机构

未公开

项目标书摘要：nnotation:Enteroviruses are ubiquitous human pathogens causing diseases with diverse clinical manifestations ranging from acute respiratory diseases to paralysis and meningitis.They are distinguished by their ability to cause epidemics,the tendency to genetic recombination with the emergence of new strains,as well as high resistance to environmental conditions,that provides their long-term persistence outside host organism.Vaccine development for the prevention of enterovirus infections(EVI)is complicated due to their high phenotypic diversity.At the same time,efforts of pharmaceutical companies in the field of direct anti-enteroviral drugs discovery with known mechanism of action and well-characterized targets were unsuccessful(for example,the drug Pleconaril,withdrawn from clinical trials).Therefore,currently,there are no approved direct antiviral drugs for EVI treatment.In that context,the aim of this project is to generate new approaches for“first in class”direct antiviral drug development in order to meet urgent medical and chemical needs.This“first in class”novel inhibitor of the enterovirus life cycle targets a new druggable site located on the surface of the viral capsid,preventing the virus from penetrating a cell.
        The starting point for this project was the pioneering research of professor J.Neyts group[1],reporting the discovery of a new interprotomer VP1-VP3 pocket in the conserved region of the enterovirus capsid surface,which represents a novel target for enterovirus replication inhibition.Derivatives of N-sulfamidobenzoic acid were identified as hit compounds and electron microscopy data on the structure of this new pocket on the enterovirus capsid surface were published paving the way for further successful medical and chemical research in the area of direct antiviral agent development.
        Our scientific group have a good methodology and a strong background in the field of sulfonamide derivatives synthesis and introduction of sulfonyl chloride and sulfonamide fragments into a wide range of diverse carbo-and heterocycles structures.This provides the grounds for the successful development of highly potent inhibitors of enteroviruses life cycle based on heteroaryl-substituted N-sulfonamidobenzoic acid derivatives.
        In the present project,cytotoxic and virus-inhibiting properties of newly synthesized derivatives of N-sulfonamidobenzoic acid will be characterized using methods of virology and molecular genetics(including the novel method of target-oriented screening of interprotomer VP1-VP3 pocket inhibitors)and their mechanism of action will be studied in detail.For the first time,data on their activity in vivo in animal model of EVI will be obtained and their calculated ADME parameters will be reported.
        In addition to the undoubted practical application,the results of the project will demonstrate a new understanding of the biology of cell penetration and life cycle of enteroviruses,lay the scientific foundations for the antiviral drug screening with a targeted range of action.Besides,organic synthesis will be replenished with new approaches to the synthesis of heterocycles containing a sulfonamide pharmacophore fragment.
        [1]PLOS Biology,2019,17(6),e3000281
        Expected results:As a result of the project implementation,the following specific results will be obtained:
        1.New synthetic approaches will be developed for the preparation of a wide pool of drug-like derivatives of N-sulfonamidobenzoic acid as a new antiviral pharmacophore acting on the capsid.Based on the original synthetic methods,more than a hundred new potential inhibitors of viral replication with a favourable set of molecular descriptors meeting the specified Drug-like criteria will be obtained and studied.
        2.A new technique for targeted screening of enterovirus replication inhibitors that bind to the interprotomeric VP1-VP3 pocket on the surface of the viral capsid will be developed.
        3.The previously synthesized and newly developed highly potent inhibitors of the viral life cycle will be investigated.Based on molecular docking and virtual screening data,a medicinal chemistry optimization of hit compounds will be carried out,which ensures the design of drug candidate molecules that include additional mechanisms of binding to the new target in the interprotomeric VP1-VP3 pocket.The results obtained will be used to construct the structure-activity relationship.
        4.In vitro data will be verified in vivo in animal model of EVI.For the lead compounds,favourable ADME parameters will be calculated.Based on the results obtained it is planned to select 2-3 of the most promising lead compounds,which will be transferred further to preclinical tests.
        5.The practical application of the obtained results will create a scientific and material platform for the discovery of"first-in-class"drug with activity against human enteroviruses,which will allow to fight effectively against a wide series of dangerous viral infections.In addition,the new fundamental data obtained will expand the scientific understanding of the capsid structure of enteroviruses.
        These data should be useful especially in demand in the Yaroslavl region,where a pharmaceutical cluster is located.This cluster includes the largest pharmaceutical companies of the Russian Federation(R-Pharm,Takeda,Teva,etc.),capable of providing investment for further project development.In addition,there are leading research centres in the region that implement a full range of pharmaceutical development.The collaboration with these centres will contribute to further project development in the framework of preclinical and clinical studies of an innovative antiviral drug candidate.
        Thus,the proposed project corresponds to the topic of the priority target of scientific and technological development of the Russian Federation“Transfer to personalized medicine,high-tech healthcare and health-preserving technologies,including through the rational use of drugs(primarily antibacterial).

Application Abstract: Annotation:Enteroviruses are ubiquitous human pathogens causing diseases with diverse clinical manifestations ranging from acute respiratory diseases to paralysis and meningitis.They are distinguished by their ability to cause epidemics,the tendency to genetic recombination with the emergence of new strains,as well as high resistance to environmental conditions,that provides their long-term persistence outside host organism.Vaccine development for the prevention of enterovirus infections(EVI)is complicated due to their high phenotypic diversity.At the same time,efforts of pharmaceutical companies in the field of direct anti-enteroviral drugs discovery with known mechanism of action and well-characterized targets were unsuccessful(for example,the drug Pleconaril,withdrawn from clinical trials).Therefore,currently,there are no approved direct antiviral drugs for EVI treatment.In that context,the aim of this project is to generate new approaches for“first in class”direct antiviral drug development in order to meet urgent medical and chemical needs.This“first in class”novel inhibitor of the enterovirus life cycle targets a new druggable site located on the surface of the viral capsid,preventing the virus from penetrating a cell.
        The starting point for this project was the pioneering research of professor J.Neyts group[1],reporting the discovery of a new interprotomer VP1-VP3 pocket in the conserved region of the enterovirus capsid surface,which represents a novel target for enterovirus replication inhibition.Derivatives of N-sulfamidobenzoic acid were identified as hit compounds and electron microscopy data on the structure of this new pocket on the enterovirus capsid surface were published paving the way for further successful medical and chemical research in the area of direct antiviral agent development.
        Our scientific group have a good methodology and a strong background in the field of sulfonamide derivatives synthesis and introduction of sulfonyl chloride and sulfonamide fragments into a wide range of diverse carbo-and heterocycles structures.This provides the grounds for the successful development of highly potent inhibitors of enteroviruses life cycle based on heteroaryl-substituted N-sulfonamidobenzoic acid derivatives.
        In the present project,cytotoxic and virus-inhibiting properties of newly synthesized derivatives of N-sulfonamidobenzoic acid will be characterized using methods of virology and molecular genetics(including the novel method of target-oriented screening of interprotomer VP1-VP3 pocket inhibitors)and their mechanism of action will be studied in detail.For the first time,data on their activity in vivo in animal model of EVI will be obtained and their calculated ADME parameters will be reported.
        In addition to the undoubted practical application,the results of the project will demonstrate a new understanding of the biology of cell penetration and life cycle of enteroviruses,lay the scientific foundations for the antiviral drug screening with a targeted range of action.Besides,organic synthesis will be replenished with new approaches to the synthesis of heterocycles containing a sulfonamide pharmacophore fragment.
        [1]PLOS Biology,2019,17(6),e3000281
        Expected results:As a result of the project implementation,the following specific results will be obtained:
        1.New synthetic approaches will be developed for the preparation of a wide pool of drug-like derivatives of N-sulfonamidobenzoic acid as a new antiviral pharmacophore acting on the capsid.Based on the original synthetic methods,more than a hundred new potential inhibitors of viral replication with a favourable set of molecular descriptors meeting the specified Drug-like criteria will be obtained and studied.
        2.A new technique for targeted screening of enterovirus replication inhibitors that bind to the interprotomeric VP1-VP3 pocket on the surface of the viral capsid will be developed.
        3.The previously synthesized and newly developed highly potent inhibitors of the viral life cycle will be investigated.Based on molecular docking and virtual screening data,a medicinal chemistry optimization of hit compounds will be carried out,which ensures the design of drug candidate molecules that include additional mechanisms of binding to the new target in the interprotomeric VP1-VP3 pocket.The results obtained will be used to construct the structure-activity relationship.
        4.In vitro data will be verified in vivo in animal model of EVI.For the lead compounds,favourable ADME parameters will be calculated.Based on the results obtained it is planned to select 2-3 of the most promising lead compounds,which will be transferred further to preclinical tests.
        5.The practical application of the obtained results will create a scientific and material platform for the discovery of"first-in-class"drug with activity against human enteroviruses,which will allow to fight effectively against a wide series of dangerous viral infections.In addition,the new fundamental data obtained will expand the scientific understanding of the capsid structure of enteroviruses.
        These data should be useful especially in demand in the Yaroslavl region,where a pharmaceutical cluster is located.This cluster includes the largest pharmaceutical companies of the Russian Federation(R-Pharm,Takeda,Teva,etc.),capable of providing investment for further project development.In addition,there are leading research centres in the region that implement a full range of pharmaceutical development.The collaboration with these centres will contribute to further project development in the framework of preclinical and clinical studies of an innovative antiviral drug candidate.
        Thus,the proposed project corresponds to the topic of the priority target of scientific and technological development of the Russian Federation“Transfer to personalized medicine,high-tech healthcare and health-preserving technologies,including through the rational use of drugs(primarily antibacterial).