A. Korovina - Academia.edu (original) (raw)
Papers by A. Korovina
Biotechnologia Acta, 2013
Analysis of study and using of different chemical compounds as inhibitors of herpes virus replica... more Analysis of study and using of different chemical compounds as inhibitors of herpes virus replication is given in the review. However, it does not apply for full details of all the studies on active antiherpetic drugs finding. It's been over 30 years since the discovery of the first antiherpetic drugs ? acyclovir. Meanwhile, lots of active chemical compounds appeared that have been brought to the antiviral drugs. An essential understanding of strategies for finding drugs came in, one of which was establishment of depot forms of antiherpetic drugs. On the basis of the vast published experimental material the authors concluded that the study of the herpes virus and search for inhibitors of its replication is still an important issue and requires the efforts of chemists, biologists, pharmacists.
Biochemistry (Moscow), 2012
Influence of the biogenic polyamines spermine, spermidine, and putrescine as well as their deriva... more Influence of the biogenic polyamines spermine, spermidine, and putrescine as well as their derivatives on the replication enzymes of hepatitis C virus (HCV) was investigated. It was found that spermine and spermidine activate HCV RNA-dependent RNA polymerase (NS5B protein). This effect was not caused by the stabilization of the enzyme or by competition with template-primer complex, but rather it was due to achievement of true maximum velocity V max. Natural polyamines and their derivatives effectively inhibited the helicase reaction catalyzed by another enzyme of HCV replication-helicase/NTPase (NS3 protein). However, these compounds affected neither the NTPase reaction nor its activation by polynucleotides. Activation of the HCV RNA polymerase and inhibition of the viral helicase were shown at physiological concentrations of the polyamines. These data suggest that biogenic polyamines may cause differently directed effects on the replication of the HCV genome in an infected cell.
Moscow University Biological Sciences Bulletin, 2020
Abstract— Gossypol is a highly active compound with antiviral, antioxidant, antimicrobial, antima... more Abstract— Gossypol is a highly active compound with antiviral, antioxidant, antimicrobial, antimalarial, and antitumor properties. It is known that the antitumor effect of gossypol is associated with genotoxicity; however, gossypol interaction with chromatin was not studied. In this work, using the method of single particle microscopy based on the Förster resonant energy transfer, it was found that gossypol at concentrations of 10 μM and higher causes significant structural changes in the conformation of nucleosomal DNA on the histone octamer. These changes affect at least 35 bp of nucleosomal DNA, increase the distance between neighboring superhelical gyres of nucleosomal DNA in this region to 9 nm or more, and are caused by unwrapping of nucleosomal DNA. The presence of linker DNA regions slightly increases the resistance of nucleosomes to the gossypol action compared with core nucleosomes. At the concentration of 30 μM and higher, gossypol completely disrupts the structure of nucleosomes, causing dissociation of histones from DNA. The obtained data indicate that gossypol genotoxicity observed in vivo could be associated with a direct effect of gossypol on chromatin, leading to disruption of the nucleosome structure.
Biochimie, 2016
The structure-function analysis of 36 methylenebisphosphonates (BPs) as inhibitors of the phospho... more The structure-function analysis of 36 methylenebisphosphonates (BPs) as inhibitors of the phosphorolytic activity of native and drug-resistant forms of HIV-1 reverse transcriptase (RT) was performed. It was shown that with the increase of the inhibitory potential of BPs towards the phosphorolytic activity raises their ability to inhibit the RT-catalyzed DNA elongation. Herein, we report the impact of the thymidine analog mutations (TAM) on the activity of bisphosphonates, as well as some structural features of the BPs, allowing them to maintain the inhibitory activity on the enzyme resistant to nucleoside analog therapy. We estimated the Mg(2+)-coordinating group structure, the linker and the aromatic pharmacophore influence on the inhibitory potential of the BPs. Based on the 31 BPs SAR, several BPs with improved inhibitory properties were designed and synthesized.
Russian Journal of Bioorganic Chemistry, 2012
ABSTRACT Inorganic pyrophosphate (PPi) is a product of the polymerization reaction catalyzed by D... more ABSTRACT Inorganic pyrophosphate (PPi) is a product of the polymerization reaction catalyzed by DNA- and RNA-polymerases. We have synthesized a number of novel non-hydrolysable PPi analogues, some of them have demonstrated inhibition of polymerization reaction catalyzed by hepatitis C virus RNA-dependent RNA-polymerase (NS5B). A new pharmacophore has been developed based on non-hydrolysable methylene-diphosphonate backbone. Structure-activity relationship analysis of 12 bisphosphonates is presented and structural features crucial for the ability of molecule to inhibit NS5B polymerase activity are ascertained.
Bioorganicheskaia khimiia
Inorganic pyrophosphate (PPi) is a product of the polymerization reaction catalyzed by DNA- and R... more Inorganic pyrophosphate (PPi) is a product of the polymerization reaction catalyzed by DNA- and RNA-polymerases. We have synthesized a number of novel non-hydrolysable PPi analogues, some of them have demonstrated inhibition of polymerization reaction catalyzed by hepatitis C virus RNA-dependent RNA-polymerase (NS5B). A new pharmacophore has been developed based on non-hydrolysable methylene-diphosphonate backbone. Structure-activity relationship analysis of 12 bisphosphonates is presented and structural features crucial for the ability of molecule to inhibit NS5B polymerase activity are ascertained.
Biochemistry (Moscow), 2014
Moscow University Chemistry Bulletin, 2008
Abstract Two types of novel nucleoside analogs have been synthesized: acyclic (Z)-and (E)-isomers... more Abstract Two types of novel nucleoside analogs have been synthesized: acyclic (Z)-and (E)-isomers of 9-[3-(phosphonometoxy) prop-1-en-1-yl] adenine and a carbocyclic isosteric analog of guanosine monophosphate. The (Z)-and (E)-isomers inhibit the replication of herpes simplex virus (HSV) and human immunodeficiency virus (HIV) and are nontoxic for cells. The (Z)-isomer activities against both viruses are higher than the (E)-isomer activities. Diphosphates of these compounds display substrate activities towards recombinant HSV ...
Molecular Biology, 2010
Проведен сравнительный анализ мутаций в генах ДНК полимераз (ul30) и тимидинкиназ (ul23) нескольк... more Проведен сравнительный анализ мутаций в генах ДНК полимераз (ul30) и тимидинкиназ (ul23) нескольких клинических изолятов вируса простого герпеса (ВПГ 1), проявляющих различную чувствительность к ряду антигерпетических препаратов, а также двух лабораторных штаммов ВПГ 1, один из которых чувствителен (L 2 ), а другой резистентен (L 2 /R) к ацикловиру (ACV). Филогенетический анализ последовательностей пока зал, что гены ul30 и ul23 клинических изолятов близки генам штамма L 2 . Установлено, что консервативные участки гена ul30 клинических изолятов ВПГ 1 и штамма L 2 отличаются только точечными мутациями и вы рожденными заменами. Сравнительный анализ первичных структур тимидинкиназы и ДНК полимеразы кли нических и лабораторных штаммов ВПГ 1 позволил идентифицировать ранее не описанные мутации в функ циональных доменах ферментов, которые обусловливают резистентность соответствующих штаммов к ACV и другим антигерпетическим препаратам.
Bioorganic Chemistry, 2010
A new class of inhibitors of herpes simplex virus replication was found. The compounds under stud... more A new class of inhibitors of herpes simplex virus replication was found. The compounds under study are derived from condensed 1,2,4-triazolo[5,1-c][1,2,4]triazines and 1,2,4-triazolo[1,5-a]pyrimidines, structural analogues of natural nucleic bases. Antiherpetic activity and cytotoxicity of the compounds were studied. The corresponding triphosphates of several active compounds were prepared and tested as inhibitors of DNA synthesis catalyzed by herpes simplex virus polymerase. The potential mechanism of their action is blocking of DNA dependent DNA polymerase, a key enzyme of viral replication.
Biochemistry (Moscow), 2012
Influence of the biogenic polyamines spermine, spermidine, and putrescine as well as their deriva... more Influence of the biogenic polyamines spermine, spermidine, and putrescine as well as their derivatives on the replication enzymes of hepatitis C virus (HCV) was investigated. It was found that spermine and spermidine activate HCV RNA-dependent RNA polymerase (NS5B protein). This effect was not caused by the stabilization of the enzyme or by competition with template-primer complex, but rather it was due to achievement of true maximum velocity V(max). Natural polyamines and their derivatives effectively inhibited the helicase reaction catalyzed by another enzyme of HCV replication - helicase/NTPase (NS3 protein). However, these compounds affected neither the NTPase reaction nor its activation by polynucleotides. Activation of the HCV RNA polymerase and inhibition of the viral helicase were shown at physiological concentrations of the polyamines. These data suggest that biogenic polyamines may cause differently directed effects on the replication of the HCV genome in an infected cell.
Biotechnologia Acta, 2013
Analysis of study and using of different chemical compounds as inhibitors of herpes virus replica... more Analysis of study and using of different chemical compounds as inhibitors of herpes virus replication is given in the review. However, it does not apply for full details of all the studies on active antiherpetic drugs finding. It's been over 30 years since the discovery of the first antiherpetic drugs ? acyclovir. Meanwhile, lots of active chemical compounds appeared that have been brought to the antiviral drugs. An essential understanding of strategies for finding drugs came in, one of which was establishment of depot forms of antiherpetic drugs. On the basis of the vast published experimental material the authors concluded that the study of the herpes virus and search for inhibitors of its replication is still an important issue and requires the efforts of chemists, biologists, pharmacists.
Biochemistry (Moscow), 2012
Influence of the biogenic polyamines spermine, spermidine, and putrescine as well as their deriva... more Influence of the biogenic polyamines spermine, spermidine, and putrescine as well as their derivatives on the replication enzymes of hepatitis C virus (HCV) was investigated. It was found that spermine and spermidine activate HCV RNA-dependent RNA polymerase (NS5B protein). This effect was not caused by the stabilization of the enzyme or by competition with template-primer complex, but rather it was due to achievement of true maximum velocity V max. Natural polyamines and their derivatives effectively inhibited the helicase reaction catalyzed by another enzyme of HCV replication-helicase/NTPase (NS3 protein). However, these compounds affected neither the NTPase reaction nor its activation by polynucleotides. Activation of the HCV RNA polymerase and inhibition of the viral helicase were shown at physiological concentrations of the polyamines. These data suggest that biogenic polyamines may cause differently directed effects on the replication of the HCV genome in an infected cell.
Moscow University Biological Sciences Bulletin, 2020
Abstract— Gossypol is a highly active compound with antiviral, antioxidant, antimicrobial, antima... more Abstract— Gossypol is a highly active compound with antiviral, antioxidant, antimicrobial, antimalarial, and antitumor properties. It is known that the antitumor effect of gossypol is associated with genotoxicity; however, gossypol interaction with chromatin was not studied. In this work, using the method of single particle microscopy based on the Förster resonant energy transfer, it was found that gossypol at concentrations of 10 μM and higher causes significant structural changes in the conformation of nucleosomal DNA on the histone octamer. These changes affect at least 35 bp of nucleosomal DNA, increase the distance between neighboring superhelical gyres of nucleosomal DNA in this region to 9 nm or more, and are caused by unwrapping of nucleosomal DNA. The presence of linker DNA regions slightly increases the resistance of nucleosomes to the gossypol action compared with core nucleosomes. At the concentration of 30 μM and higher, gossypol completely disrupts the structure of nucleosomes, causing dissociation of histones from DNA. The obtained data indicate that gossypol genotoxicity observed in vivo could be associated with a direct effect of gossypol on chromatin, leading to disruption of the nucleosome structure.
Biochimie, 2016
The structure-function analysis of 36 methylenebisphosphonates (BPs) as inhibitors of the phospho... more The structure-function analysis of 36 methylenebisphosphonates (BPs) as inhibitors of the phosphorolytic activity of native and drug-resistant forms of HIV-1 reverse transcriptase (RT) was performed. It was shown that with the increase of the inhibitory potential of BPs towards the phosphorolytic activity raises their ability to inhibit the RT-catalyzed DNA elongation. Herein, we report the impact of the thymidine analog mutations (TAM) on the activity of bisphosphonates, as well as some structural features of the BPs, allowing them to maintain the inhibitory activity on the enzyme resistant to nucleoside analog therapy. We estimated the Mg(2+)-coordinating group structure, the linker and the aromatic pharmacophore influence on the inhibitory potential of the BPs. Based on the 31 BPs SAR, several BPs with improved inhibitory properties were designed and synthesized.
Russian Journal of Bioorganic Chemistry, 2012
ABSTRACT Inorganic pyrophosphate (PPi) is a product of the polymerization reaction catalyzed by D... more ABSTRACT Inorganic pyrophosphate (PPi) is a product of the polymerization reaction catalyzed by DNA- and RNA-polymerases. We have synthesized a number of novel non-hydrolysable PPi analogues, some of them have demonstrated inhibition of polymerization reaction catalyzed by hepatitis C virus RNA-dependent RNA-polymerase (NS5B). A new pharmacophore has been developed based on non-hydrolysable methylene-diphosphonate backbone. Structure-activity relationship analysis of 12 bisphosphonates is presented and structural features crucial for the ability of molecule to inhibit NS5B polymerase activity are ascertained.
Bioorganicheskaia khimiia
Inorganic pyrophosphate (PPi) is a product of the polymerization reaction catalyzed by DNA- and R... more Inorganic pyrophosphate (PPi) is a product of the polymerization reaction catalyzed by DNA- and RNA-polymerases. We have synthesized a number of novel non-hydrolysable PPi analogues, some of them have demonstrated inhibition of polymerization reaction catalyzed by hepatitis C virus RNA-dependent RNA-polymerase (NS5B). A new pharmacophore has been developed based on non-hydrolysable methylene-diphosphonate backbone. Structure-activity relationship analysis of 12 bisphosphonates is presented and structural features crucial for the ability of molecule to inhibit NS5B polymerase activity are ascertained.
Biochemistry (Moscow), 2014
Moscow University Chemistry Bulletin, 2008
Abstract Two types of novel nucleoside analogs have been synthesized: acyclic (Z)-and (E)-isomers... more Abstract Two types of novel nucleoside analogs have been synthesized: acyclic (Z)-and (E)-isomers of 9-[3-(phosphonometoxy) prop-1-en-1-yl] adenine and a carbocyclic isosteric analog of guanosine monophosphate. The (Z)-and (E)-isomers inhibit the replication of herpes simplex virus (HSV) and human immunodeficiency virus (HIV) and are nontoxic for cells. The (Z)-isomer activities against both viruses are higher than the (E)-isomer activities. Diphosphates of these compounds display substrate activities towards recombinant HSV ...
Molecular Biology, 2010
Проведен сравнительный анализ мутаций в генах ДНК полимераз (ul30) и тимидинкиназ (ul23) нескольк... more Проведен сравнительный анализ мутаций в генах ДНК полимераз (ul30) и тимидинкиназ (ul23) нескольких клинических изолятов вируса простого герпеса (ВПГ 1), проявляющих различную чувствительность к ряду антигерпетических препаратов, а также двух лабораторных штаммов ВПГ 1, один из которых чувствителен (L 2 ), а другой резистентен (L 2 /R) к ацикловиру (ACV). Филогенетический анализ последовательностей пока зал, что гены ul30 и ul23 клинических изолятов близки генам штамма L 2 . Установлено, что консервативные участки гена ul30 клинических изолятов ВПГ 1 и штамма L 2 отличаются только точечными мутациями и вы рожденными заменами. Сравнительный анализ первичных структур тимидинкиназы и ДНК полимеразы кли нических и лабораторных штаммов ВПГ 1 позволил идентифицировать ранее не описанные мутации в функ циональных доменах ферментов, которые обусловливают резистентность соответствующих штаммов к ACV и другим антигерпетическим препаратам.
Bioorganic Chemistry, 2010
A new class of inhibitors of herpes simplex virus replication was found. The compounds under stud... more A new class of inhibitors of herpes simplex virus replication was found. The compounds under study are derived from condensed 1,2,4-triazolo[5,1-c][1,2,4]triazines and 1,2,4-triazolo[1,5-a]pyrimidines, structural analogues of natural nucleic bases. Antiherpetic activity and cytotoxicity of the compounds were studied. The corresponding triphosphates of several active compounds were prepared and tested as inhibitors of DNA synthesis catalyzed by herpes simplex virus polymerase. The potential mechanism of their action is blocking of DNA dependent DNA polymerase, a key enzyme of viral replication.
Biochemistry (Moscow), 2012
Influence of the biogenic polyamines spermine, spermidine, and putrescine as well as their deriva... more Influence of the biogenic polyamines spermine, spermidine, and putrescine as well as their derivatives on the replication enzymes of hepatitis C virus (HCV) was investigated. It was found that spermine and spermidine activate HCV RNA-dependent RNA polymerase (NS5B protein). This effect was not caused by the stabilization of the enzyme or by competition with template-primer complex, but rather it was due to achievement of true maximum velocity V(max). Natural polyamines and their derivatives effectively inhibited the helicase reaction catalyzed by another enzyme of HCV replication - helicase/NTPase (NS3 protein). However, these compounds affected neither the NTPase reaction nor its activation by polynucleotides. Activation of the HCV RNA polymerase and inhibition of the viral helicase were shown at physiological concentrations of the polyamines. These data suggest that biogenic polyamines may cause differently directed effects on the replication of the HCV genome in an infected cell.