scholarly journals MODERN ETHIOTROPIC CHEMOTHERAPY OF HUMAN CYTOMEGALOVIRUS INFECTION: CLINICAL EFFECTIVENESS, MOLECULAR MECHANISM OF ACTION, DRUG RESISTANCE, NEW TRENDS AND PROSPECTS. PART 1

2018 ◽  
Vol 63 (5) ◽  
pp. 202-211
Author(s):  
V. L. Andronova
Keyword(s):  
Drug Resistance ◽  
Dna Polymerase ◽  
Antiviral Agents ◽  
Clinical Effectiveness ◽  
Structural Features ◽  
Modified Nucleosides ◽  
Second Line ◽  
Molecular Mechanism Of Action ◽  
Human Cytomegalovirus Infection ◽  
New Compounds

Modern chemotherapy of cytomegalovirus (CMV) infections has a very limited arsenal of first-line drugs. These are preparations of ganciclovir (GCV) belonging to the class of modified nucleosides and its metabolic precursor ganciclovir valine ester. After three-step phosphorylation, GCV, as a structural analogue of the natural nucleotide, competes with it for binding to DNA polymerase and, due to its structural features, inhibits its activity. However, with prolonged use of GCV, mainly under conditions of immunosuppression, the virus develops drug resistance associated in most cases with changes in pUL97 catalyzing the first stage of GCV phosphorylation, as well as in the catalytic subunit of DNA polymerase. When variants of viruses resistant to GCV appear, second-line drugs are used: pyrophosphate analog of foscarnet and nucleotide cidofovir. Resistance to second-line drugs is due to mutations in the pol-gene and in a number of cases leads to multiresistance, which makes it impossible to use traditional anti-CMV drugs. In addition, the use of all of the above drugs is accompanied by the development of severe side effects. All of the above determines the need to search for new compounds that can effectively inhibit the reproduction of the virus, harmless to the macroorganism, convenient to use, overcoming the drug resistance barrier in viruses. As a result of the search in international databases (PubMed, MedLine, eLIBRARY.RU, ClinicalTrials.gov, etc.), the main trends in the search for new anti-CMV agents were identified. In the first part of the review, we concentrated on compounds that are modifications of known antiviral agents currently used in clinical practice, the most promising for the development of drug anti-CMV drugs.

scholarly journals MODERN ETHIOTROPIC CHEMOTHERAPY OF HERPESVIRUS INFECTIONS: ADVANCES, NEW TRENDS AND PERSPECTIVES. ALPHAHERPESVIRINAE (part I)

2018 ◽  
Vol 63 (3) ◽  
pp. 106-114
Author(s):  
V. L. Andronova
Keyword(s):  
Drug Resistance ◽  
Biological Activity ◽  
Dna Polymerase ◽  
Antiviral Agents ◽  
Structural Features ◽  
Modern Medicine ◽  
Antiviral Drugs ◽  
Modified Nucleosides ◽  
Herpesvirus Infection ◽  
New Compounds

Modern therapy of infections caused by alpha-herpesviruses is based on drugs belonging to the class of modified nucleosides (acyclovir) and their metabolic progenitors - valine ester of acyclovir and famciclovir (prodrug of penciclovir). The biological activity of these compounds is determined by the similarity of their structure to natural nucleosides: modified nucleosides compete with natural nucleosides for binding to DNA-polymerase and, due to their structural features, inhibit its activity. However, the emergence of variants of viruses resistant to the antiviral drugs available in the arsenal of modern medicine necessitates the search for new compounds able of effectively inhibiting the reproduction of viruses. These compounds should be harmless to the macroorganisms, convenient to use, and overcoming the drug resistance barrier in viruses. The search for literature in international databases (PubMed, MedLine, RINC, etc.) in order to obtain information on promising developments that open new possibilities for treating herpesvirus infection and subsequent analysis of the collected data made it possible to determine not only the main trends in the search for new antiviral agents, but also to provide information on the compounds most promising for the development of anti-herpesvirus drugs.

scholarly journals MODERN ETHIOTROPIC CHEMOTHERAPY OF HERPESVIRUS INFECTIONS: ADVANCES, NEW TRENDS AND PERSPECTIVES. ALPHAHERPESVIRUSES (PART II)

2018 ◽  
Vol 63 (4) ◽  
pp. 149-159
Author(s):  
V. L. Andronova
Keyword(s):  
Drug Resistance ◽  
Biological Activity ◽  
Dna Polymerase ◽  
Viral Proteins ◽  
Modified Nucleosides ◽  
Cellular Proteins ◽  
Viral Dna ◽  
Biological Target ◽  
New Compounds

A key role in the treatment of herpesviral infections is played by modified nucleosides and their predecessors - acyclovir, its L-valine ester (valaciclovir) and famciclovir (prodrug of penciclovir). The biological activity of compounds of this class is determined by their similarity to natural nucleosides. After phosphorylation by viral thymidine kinase and then cell enzymes to the triphosphate forms, acyclovir and penciclovir inhibit the activity of viral DNA polymerase and synthesis of viral DNA. The increasing role of herpesvirus infections in human infectious pathology, as well as the development of drug resistance in viruses, mainly in patients with immunodeficiencies of various origins, necessitate the search for new compounds possessing anti-herpesvirus activity, using as a biological target not DNA polymerase, but other viral proteins and enzymes, unique or different from cellular proteins, performing similar functions.

scholarly journals MODERN ETHIOTROPIC CHEMOTHERAPY OF HUMAN CYTOMEGALOVIRUS INFECTION: CLINICAL EFFECTIVENESS, MOLECULAR MECHANISM OF ACTION, DRUG RESISTANCE, NEW TRENDS AND PROSPECTS. PART 2

2018 ◽  
Vol 63 (6) ◽  
pp. 250-260
Author(s):  
V. L. Andronova
Keyword(s):  
Drug Resistance ◽  
Human Cytomegalovirus ◽  
Clinical Effectiveness ◽  
Great Activity ◽  
Third Phase ◽  
Viral Cyclin ◽  
Preclinical Trials ◽  
Molecular Mechanism Of Action ◽  
Resistant Strains ◽  
Human Cmv

A number of synthetic compounds, such as the nucleoside analog ganciclovir, its L-valine ester (a metabolic precursor of ganciclovir) and pyrophosphate analog foscarnet, are permitted for the treatment of HCMV-related diseases in the WHO European Region. The viral DNA- polymerase is used by all these drugs as a bio-target. However, the usage of standard anti-CMV therapy is accompanied by severe side effects, as well as the development of drug resistance in the virus, mainly in conditions of immunodeficiency. In this review, we focused on viral proteins of interest as new potential targets and their inhibitors, such as the inhibitor of human CMV terminology, lethermovir, which showed great activity in the third phase of clinical trials, inhibitors of viral cyclin-dependent kinase (maribavir, cyclopropavir ) and a number of compounds exhibiting anti-HCMV-activity, undergoing only preclinical trials in the experiment. Inclusion of new anti-CMV agents that are active against GСV/PFA/CDV-resistant strains of CMV into standard prophylactic and therapeutic regimens, will allow to increase the effectiveness of anti-CMV therapy, including in cases when standard therapy is ineffective. Areas covered: the international databases such as A MEDLINE, PubMed, eLIBRARY.RU, ClinicalTrials.gov., etc. with the purpose of obtaining information on compounds showing selective action against the human cytomegalovirus, the most promising for the development of drugs.

scholarly journals Characterization of Drug Resistance-Associated Mutations in the Human Cytomegalovirus DNA Polymerase Gene by Using Recombinant Mutant Viruses Generated from Overlapping DNA Fragments

1998 ◽  
Vol 72 (7) ◽  
pp. 5927-5936 ◽  
Author(s):  
Tomas Cihlar ◽  
Michael D. Fuller ◽  
Julie M. Cherrington
Keyword(s):  
Drug Resistance ◽  
Dna Polymerase ◽  
Human Cytomegalovirus ◽  
Antiviral Agents ◽  
Point Mutations ◽  
Drug Susceptibility ◽  
Dna Fragments ◽  
Conserved Regions ◽  
Susceptibility Profiles ◽  
Region Ii

ABSTRACT A number of specific point mutations in the human cytomegalovirus (HCMV) DNA polymerase (UL54) gene have been tentatively associated with decreased susceptibility to antiviral agents and consequently with clinical failure. To precisely determine the roles of UL54 mutations in HCMV drug resistance, recombinant UL54 mutant viruses were generated by using cotransfection of nine overlapping HCMV DNA fragments into permissive fibroblasts, and their drug susceptibility profiles were determined. Amino acid substitutions located in UL54 conserved region IV (N408D, F412C, and F412V), region V (A987G), and δ-region C (L501I, K513E, P522S, and L545S) conferred various levels of resistance to cidofovir and ganciclovir. Mutations in region II (T700A and V715M) and region VI (V781I) were associated with resistance to foscarnet and adefovir. The region II mutations also conferred moderate resistance to lobucavir. In contrast to mutations in other UL54 conserved regions, those residing specifically in region III (L802M, K805Q, and T821I) were associated with various drug susceptibility profiles. Mutations located outside the known UL54 conserved regions (S676G and V759M) did not confer any significant changes in HCMV drug susceptibility. Predominantly an additive effect of multiple UL54 mutations with respect to the final drug resistance phenotype was demonstrated. Finally, the influence of selected UL54 mutations on the susceptibility of viral DNA replication to antiviral drugs was characterized by using a transient-transfection-plus-infection assay. Results of this work exemplify specific roles of the UL54 conserved regions in the development of HCMV drug resistance and may help guide optimization of HCMV therapy.

Recent Advances towards Drug Design Targeting the Protease of 2019 novel coronavirus (2019-nCoV)

2020 ◽  
Vol 27 ◽  
Author(s):  
Sehrish Bano ◽  
Abdul Hameed ◽  
Mariya Al-Rashida ◽  
Shafia Iftikhar ◽  
Jamshed Iqbal
Keyword(s):  
Drug Design ◽  
Rna Polymerase ◽  
Drug Targets ◽  
Antiviral Agents ◽  
Structural Features ◽  
Antiviral Drugs ◽  
Rna Dependent Rna Polymerase ◽  
Mortality And Morbidity ◽  
Functional Relationships ◽  
Novel Coronavirus

Background: The 2019 novel coronavirus (2019-nCoV), also known as coronavirus 2 (SARS-CoV-2) acute respiratory syndrome has recently emerged and continued to spread rapidly with high level of mortality and morbidity rates. Currently, no efficacious therapy is available to relieve coronavirus infections. As new drug design and development takes much time, there is a possibility to find an effective treatment from existing antiviral agents. Objective: In this case, there is a need to find out the relationship between possible drug targets and mechanism of action of antiviral drugs. This review discusses about the efforts to develop drug from known or new molecules. Methods: Viruses usually have two structural integrities, proteins and nucleic acids, both of which can be possible drug targets. Herein, we systemically discuss the structural-functional relationships of the spike, 3-chymotrypsin-like protease (3CLpro), papain like protease (PLpro) and RNA-dependent RNA polymerase (RdRp), as these are prominent structural features of corona virus. Certain antiviral drugs such as Remdesivir are RNA dependent RNA polymerase inhibitor. It has the ability to terminate RNA replication by inhibiting ATP. Results: It is reported that ATP is involved in synthesis of coronavirus non-structural proteins from 3CLpro and PLpro. Similarly, mechanisms of action of many other antiviral agents has been discussed in this review. It will provide new insights into the mechanism of inhibition, and let us develop new therapeutic antiviral approaches against novel SARS-CoV-2 coronavirus. Conclusion: In conclusion, this review summarizes recent progress in developing protease inhibitors for SARS-CoV-2.

scholarly journals 4,7-Disubstituted 7H-Pyrrolo[2,3-d]pyrimidines and Their Analogs as Antiviral Agents against Zika Virus

Molecules ◽  
2021 ◽  
Vol 26 (13) ◽  
pp. 3779
Author(s):  
Ruben Soto-Acosta ◽  
Eunkyung Jung ◽  
Li Qiu ◽  
Daniel J. Wilson ◽  
Robert J. Geraghty ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Dengue Virus ◽  
Small Molecules ◽  
Zika Virus ◽  
Antiviral Agents ◽  
Structural Features ◽  
Molecular Target ◽  
Core Structure ◽  
Human Pathogens ◽  
Important Group

Discovery of compound 1 as a Zika virus (ZIKV) inhibitor has prompted us to investigate its 7H-pyrrolo[2,3-d]pyrimidine scaffold, revealing structural features that elicit antiviral activity. Furthermore, we have demonstrated that 9H-purine or 1H-pyrazolo[3,4-d]pyrimidine can serve as an alternative core structure. Overall, we have identified 4,7-disubstituted 7H-pyrrolo[2,3-d]pyrimidines and their analogs including compounds 1, 8 and 11 as promising antiviral agents against flaviviruses ZIKV and dengue virus (DENV). While the molecular target of these compounds is yet to be elucidated, 4,7-disubstituted 7H-pyrrolo[2,3-d]pyrimidines and their analogs are new chemotypes in the design of small molecules against flaviviruses, an important group of human pathogens.

scholarly journals Increasing prevalence of resistance to second-line drugs among multidrug-resistant Mycobacterium tuberculosis isolates in Kuwait

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Noura M. Al-Mutairi ◽  
Suhail Ahmad ◽  
Eiman Mokaddas
Keyword(s):  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Mutation Detection ◽  
Susceptibility Testing ◽  
Multidrug Resistant ◽  
Genetic Mutations ◽  
Second Line ◽  
Injectable Drugs ◽  
Mdr Tb ◽  
Phenotypic Susceptibility

AbstractMolecular methods detect genetic mutations associated with drug resistance. This study detected resistance-conferring mutations in gyrA/gyrB for fluoroquinolones and rrs/eis genes for second-line injectable drugs (SLIDs) among multidrug-resistant Mycobacterium tuberculosis (MDR-TB) isolates in Kuwait. Fifty pansusceptible M. tuberculosis and 102 MDR-TB strains were tested. Phenotypic susceptibility testing was performed by MGIT 960 system using SIRE drug kit. GenoType MTBDRsl version 1 (gMTBDRslv1) and GenoType MTBDRsl version 2 (gMTBDRslv2) tests were used for mutation detection. Results were validated by PCR-sequencing of respective genes. Fingerprinting was performed by spoligotyping. No mutations were detected in pansusceptible isolates. gMTBDRslv1 detected gyrA mutations in 12 and rrs mutations in 8 MDR-TB isolates. gMTBDRsl2 additionally detected gyrB mutations in 2 and eis mutation in 1 isolate. Mutations in both gyrA/gyrB and rrs/eis were not detected. gMTBDRslv1 also detected ethambutol resistance-conferring embB mutations in 59 isolates. Although XDR-TB was not detected, frequency of resistance-conferring mutations for fluoroquinolones or SLIDs was significantly higher among isolates collected during 2013–2019 versus 2006–2012. Application of both tests is warranted for proper management of MDR-TB patients in Kuwait as gMTBDRslv2 detected resistance to fluoroquinolones and/or SLIDs in 3 additional isolates while gMTBDRslv1 additionally detected resistance to ethambutol in 58% of MDR-TB isolates.

Exploring the Contribution of Mycobacteria Characteristics in Their Interaction with Human Macrophages

2013 ◽  
Vol 19 (5) ◽  
pp. 1159-1169 ◽  
Author(s):  
Carla Silva ◽  
Joao Perdigao ◽  
Elsa Alverca ◽  
António P. Alves de Matos ◽  
Patricia A. Carvalho ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cell Envelope ◽  
Treatment Strategies ◽  
Human Monocyte ◽  
Selective Advantage ◽  
Multidrug Resistant ◽  
Structural Features ◽  
Major Health Problem ◽  
Transmission Electron ◽  
Mdr Tb

AbstractTuberculosis (TB) is a major health problem. The emergence of multidrug resistant (MDR)Mycobacterium tuberculosis(Mtb) isolates confounds treatment strategies. In Portugal, cases of MDR-TB are reported annually with an increased incidence noted in Lisbon. The majority of these MDR-TB cases are due to closely related mycobacteria known collectively as theLisboafamily and Q1 cluster. Genetic determinants linked to drug resistance have been exhaustively studied resulting in the identification of family and cluster specific mutations. Nevertheless, little is known about other factors involved in development of mycobacteria drug resistance. Here, we complement genetic analysis with the study of morphological and structural features of theLisboafamily and Q1 cluster isolates by using scanning and transmission electron microscopy. This analysis allowed the identification of structural differences, such as cell envelope thickness, between Mtb clinical isolates that are correlated with antibiotic resistance. The infection of human monocyte derived macrophages allowed us to document the relative selective advantage of theLisboafamily isolates over other circulating Mtb isolates.

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