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 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. 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.

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 Binary Mixtures of (N-phosphonomethyl)-glycine with New Aminophosphonates

2004 ◽  
Vol 59 (7-8) ◽  
pp. 515-518 ◽  
Author(s):  
Krzysztof Bielecki ◽  
Janusz Sarapuk ◽  
Halina Kleszczynáska
Keyword(s):  
Biological Activity ◽  
Binary Mixtures ◽  
Structural Features ◽  
Wheat Growth ◽  
Inhibition Of Growth ◽  
Additive Type ◽  
Order Of Magnitude ◽  
Organophosphorous Compounds ◽  
New Compounds ◽  
Potential Use

AbstractThe potential biological activity of binary mixtures of some new organophosphorous compounds, aminoalkane- and aminofluorenephosphonates, with (N-phosphonomethyl)-glycine (glyphosate, PMG) was studied. The inhibition of growth of wheat (Triticum aestivum) induced by individual compounds and their equimolar mixtures with PMG was a measure of that activity. The experiments were expected to show if the new compounds exhibited good biological activity to be used for agrochemical applications and if this activity can be improved when they are used in mixtures with glyphosate which is the active component of the well-known herbicide Roundup. The results obtained show that aminofluorenephosphonates inhibited wheat growth when used in micromolar concentrations. Thus, their efficiency can be compared to that of PMG. The efficiency of aminoalkanephosphonates was one order of magnitude weaker. The measure of the efficiency was the effective concentration inhibiting wheat growth by 50% (EC50). The most demanded interaction, i.e., a synergistic was observed for only one of binary mixtures of the compounds studied with PMG. Mostly they showed antagonistic or strong antagonistic interactions. Some of them were of the additive type. Such results exclude the possibility of potential use of all the compounds studied in binary mixtures with phosphonomethylglycine, especially as the mentioned synergistic interaction found was rather weak. The influence of structural features of aminophosphonates on the results obtained is discussed.

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.

scholarly journals Targeting of Regulators as a Promising Approach in the Search for Novel Antimicrobial Agents

2022 ◽  
Vol 10 (1) ◽  
pp. 185
Author(s):  
Davide Roncarati ◽  
Vincenzo Scarlato ◽  
Andrea Vannini
Keyword(s):  
Biological Activity ◽  
Antibiotic Treatment ◽  
Bacterial Infections ◽  
Scientific Community ◽  
Antimicrobial Agents ◽  
Modern Medicine ◽  
High Potential ◽  
New Drugs ◽  
New Antibiotics ◽  
New Compounds

Since the discovery of penicillin in the first half of the last century, antibiotics have become the pillars of modern medicine for fighting bacterial infections. However, pathogens resistant to antibiotic treatment have increased in recent decades, and efforts to discover new antibiotics have decreased. As a result, it is becoming increasingly difficult to treat bacterial infections successfully, and we look forward to more significant efforts from both governments and the scientific community to research new antibacterial drugs. This perspective article highlights the high potential of bacterial transcriptional and posttranscriptional regulators as targets for developing new drugs. We highlight some recent advances in the search for new compounds that inhibit their biological activity and, as such, appear very promising for treating bacterial infections.

Recent Advances in the Discovery of Antiviral Metabolites from Fungi

2021 ◽  
Vol 22 ◽  
Author(s):  
Sunil K. Deshmukh ◽  
Shivankar Agrawal ◽  
Manish Kumar Gupta ◽  
Rajesh K. Patidar ◽  
Nihar Ranjan
Keyword(s):  
Secondary Metabolites ◽  
Treatment Options ◽  
Antiviral Agents ◽  
Antiviral Drugs ◽  
Plant Diseases ◽  
Dna And Rna ◽  
Global Pandemic ◽  
Wide Range ◽  
New Compounds ◽  
The Impact

: As the world manages the impact of a global pandemic caused by COVID-19, the discovery of new antiviral agents has become way more relevant and urgent. Viruses are submicroscopic infectious agents that replicate inside the living cells of different organisms. These viruses use nucleic acids (both DNA and RNA) for further replication and maturity inside the cells. Some of the viruses responsible for various human and plant diseases belong to the classes of Picornaviridae, Retroviridae, Orthomyxoviridae, Flaviviridae, Pneumoviridae, Virgaviridae, and Hepadnaviridae, and their treatment options are limited or non-existent. The consistent reemergence and resistance development in the viral strains demands the discovery and development of new antiviral drugs possessing better efficacy. Bio-active compounds isolated from fungi can be the source of new compounds with enhanced potency and new mechanisms of action. Fungi are known to produce a diverse lot of secondary metabolites due to their existence in harsh climates which are often inhabitable for many organisms. Due to these unique environments, fungi produce a variety of secondary metabolites of different chemical classes like alkaloids, quinones, furanone, pyrones, benzopyranoids, xanthones, terpenes, steroids, peptides, and many acyclic compounds. Fungal metabolites are known to display a wide range of bioactive attributes, i.e., anticancer, antibacterial, antifungal, and anti-Alzheimer's, along with antiviral properties. In this review article, we report over 300 antiviral compounds from fungal sources during the period of 2009 to 2019. The source of these compounds is marine and endophytic fungi and they are arranged based on their antiviral action against different viral families. These compounds are promising in their use and development as future antiviral drugs.

The gut microbiota resistome provides development of drug resistance in causative agents of human infectious diseases

2017 ◽  
pp. 20-32 ◽  
Author(s):  
Е.Н. Ильина ◽  
Е.И. Олехнович ◽  
А.В. Павленко
Keyword(s):  
Drug Resistance ◽  
Antibiotic Resistance ◽  
Resistance Genes ◽  
Integrated Approach ◽  
Modern Medicine ◽  
Pathogenic Microorganisms ◽  
Human Pathogens ◽  
Potential Source ◽  
Causative Agents ◽  
Bacterial Genes

С течением времени подходы к изучению резистентности к антибиотикам трансформировались от сосредоточения на выделенных в виде чистой культуры патогенных микроорганизмах к исследованию резистентности на уровне микробных сообществ, составляющих биотопы человека и окружающей среды. По мере того, как продвигается изучение устойчивости к антибиотикам, возникает необходимость использования комплексного подхода для улучшения информирования мирового сообщества о наблюдаемых тенденциях в этой области. Все более очевидным становится то, что, хотя не все гены резистентности могут географически и филогенетически распространяться, угроза, которую они представляют, действительно серьезная и требует комплексных междисциплинарных исследований. В настоящее время резистентность к антибиотикам среди патогенов человека стала основной угрозой в современной медицине, и существует значительный интерес к определению ниши, в которых бактерии могут получить гены антибиотикорезистентности, и механизмов их передачи. В данном обзоре мы рассматриваем проблемы, возникшие на фоне широкого использования человечеством антибактериальных препаратов, в свете формирования микрофлорой кишечника резервуара генов резистентности. Over the time, studies of antibiotic resistance have transformed from focusing on pathogenic microorganisms isolated as a pure culture to analysis of resistance at the level of microbial communities that constitute human and environmental biotopes. Advancing studies of antibiotic resistance require an integrated approach to enhance availability of information about observed tendencies in this field to the global community. It becomes increasingly obvious that, even though not all resistance genes can geographically and phylogenetically spread, the threat they pose is indeed serious and requires complex interdisciplinary research. Currently, the antibiotic resistance of human pathogens has become a challenge to modern medicine, which is now focusing on determining a potential source for bacterial genes of drug resistance and mechanisms for the gene transmission. In this review, we discussed problems generated by the widespread use of antibacterial drugs in the light of forming a reservoir of resistance genes by gut microflora.

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 Development of Antibacterial and Antifungal Triazole Chromium(III) and Cobalt(II) Complexes: Synthesis and Biological Activity Evaluations

Molecules ◽  
2018 ◽  
Vol 23 (8) ◽  
pp. 2013 ◽  
Author(s):  
Ricardo Murcia ◽  
Sandra Leal ◽  
Martha Roa ◽  
Edgar Nagles ◽  
Alvaro Muñoz-Castro ◽  
...  
Keyword(s):  
Electrical Conductivity ◽  
Biological Activity ◽  
Melting Point ◽  
Inhibitory Concentration ◽  
Vero Cells ◽  
Visible Spectroscopy ◽  
Antifungal Activities ◽  
Antibacterial And Antifungal Activities ◽  
Antibacterial And Antifungal ◽  
New Compounds

In this work, six complexes (2–7) of Cr(III) and Co(II) transition metals with triazole ligands were synthesized and characterized. In addition, a new ligand, 3,5-bis(1,2,4-triazol-1-ylmethyl)toluene (1), was synthesized and full characterized. The complexes were obtained as air-stable solids and characterized by melting point, electrical conductivity, thermogravimetric analysis, and Raman, infrared and ultraviolet/visible spectroscopy. The analyses and spectral data showed that complexes 3–7 had 1:1 (M:L) stoichiometries and octahedral geometries, while 2 had a 1:2 (M:L) ratio, which was supported by DFT calculations. The complexes and their respective ligands were evaluated against bacterial and fungal strains with clinical relevance. All the complexes showed higher antibacterial and antifungal activities than the free ligands. The complexes were more active against fungi than against bacteria. The activities of the chromium complexes against Candida tropicalis are of great interest, as they showed minimum inhibitory concentration 50 (MIC50) values between 7.8 and 15.6 μg mL−1. Complexes 5 and 6 showed little effect on Vero cells, indicating that they are not cytotoxic. These results can provide an important platform for the design of new compounds with antibacterial and antifungal activities.

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