scholarly journals In silicodesign of glyco-D,L-peptide antiviral molecules

2019 ◽  
Author(s):  
Luigi Agostini ◽  
Stefano Morosetti
Keyword(s):  
Binding Constant ◽  
Antiviral Agents ◽  
Specific Interaction ◽  
Nucleoside Analogs ◽  
Md Simulations ◽  
Enzymatic Digestion ◽  
Peptide Molecule ◽  
Gp120 Glycoprotein ◽  
Hiv Envelope ◽  
Viral Surface

AbstractBackgroundmost licensed antiviral drugs are nucleoside analogs. A recent research focuses on blocking a virus from entering the cells in the viral cell adsorption/entry stage. In this entry mechanism the glycans present on the viral surface play a fundamental role. Homochiral L-peptides acting this fusion mechanism have shown some inhibition of viral infection. Peptides with regularly alternating enantiomeric sequence (L,D-peptides) can assume structures, which are not accessible to the corresponding homochiral molecules. Further, L,D-peptides are less sensitive to the enzymatic digestion.Aimin silicodesign a L,D-peptide with a high affinity for the viral surface glycans, and consequently able to interfere with its fusion mechanism.Methodsa 3α,6α-Mannopentaose (3-6MP) molecule was used to simulate a viral surface glycan. Molecular Dynamics (MD) simulations of 3-6MP and D,L-peptide in water are performed using the force field AMBER12-GLYCAM06i. The binding constant was evaluated from trajectories. The D,L-peptide molecule was modified over the sequence, the length, the terminals and finally glycosylated to attain a very high binding constant value for 3-6MP.In addition, the specific interaction between T lymphocyte CD4 glycoprotein and HIV envelope gp120 glycoprotein was studied through MD simulations between a D,L-peptide, bounded to a typical CD4 glycan, and a highly conserved HIV gp120 glycan.Resultsin the case of interaction with 3-6MP molecule, the very effective molecule obtained was H-D-Trp-L-Pro-D-Asn-L-Pro-D-Trp-L-Pro-D-Asn-L-Pro-OH where the Asn residues in position 3 and 7 are glycosylated with alpha-D-Mannopyranosyl-(1->3)-[alpha-D-mannopyranosyl-(1->6)]-alpha-D-mannopyranosyl-(1->4)-N-acetyl-beta-D-glucopyranosyl-(1->4)-N-acetyl-beta-D-glucopyranosyl-1-OH.In the case of interaction with HIV envelope, the very effective molecule obtained, able to antagonize the CD4 glycoprotein, was H-D-Trp-L-Pro-D-Asn-L-Pro-D-Trp-L-Pro-D-Asn-L-Pro-OH where the Asn residue in position 3 is glycosylated with alpha-D-galactopyranosyl-(1->4)-N-acetyl-beta-D-glucopyranosyl-(1->2)-alpha-D-Mannopyranosyl-(1->3)-[alpha-D-galactopyranosyl-(1->4)-N-acetyl-beta-D-glucopyranosyl-(1->2)-alpha-D-Mannopyranosyl-(1->6)]-beta-D-mannopyranosyl-(1->4)-N-acetyl-beta-D-glucopyranosyl-(1->4)-N-acetyl-beta-D-glucopyranosyl-1-OHConclusionthese glycosylated D,L-peptide molecules are very promising representatives of a new class of antiviral agents.

Ribavirin

PEDIATRICS ◽  
1987 ◽  
Vol 79 (2) ◽  
pp. 289-291
Author(s):  
DAVID ISAACS
Keyword(s):  
Thymidine Kinase ◽  
Antibacterial Agents ◽  
Antiviral Agents ◽  
Nucleoside Analogs ◽  
Viral Diseases ◽  
Herpes Viruses ◽  
Important Advance ◽  
Dna Viruses ◽  
Low Toxicity ◽  
Simplex Virus

Immunization has proved to be the most effective way of controlling viral diseases, and the development of antiviral drugs has lagged behind the development of antibacterial agents. Many of the early antiviral agents were DNA nucleoside analogs such as idoxuridine, cytarabine, and vidarabine, which competitively inhibited replication of DNA viruses, especially herpes viruses. An important advance was the deliberate synthesis of a purine nucleoside analog, acyclovir, which is only active following phosphorylation, which is carried out selectively by virus-coded thymidine kinase. Acyclovir is active against some herpesviruses, particularly herpes simplex virus, but not against RNA viruses, and appears to have low toxicity because of the low level of phosphorylation by host cell thymidine kinase.

scholarly journals Nucleoside Analogs with Selective Antiviral Activity against Dengue Fever and Japanese Encephalitis Viruses

2019 ◽  
Vol 63 (7) ◽  
Author(s):  
Keivan Zandi ◽  
Leda Bassit ◽  
Franck Amblard ◽  
Bryan D. Cox ◽  
Pouya Hassandarvish ◽  
...  
Keyword(s):  
Japanese Encephalitis ◽  
Viral Infections ◽  
Antiviral Agents ◽  
Public Health Problem ◽  
Nucleoside Analogs ◽  
Global Public Health ◽  
Direct Acting Antiviral ◽  
East And Southeast Asia ◽  
Direct Acting ◽  
Global Public Health Problem

ABSTRACTDengue virus (DENV) and Japanese encephalitis virus (JEV) are important arthropod-borne viruses from theFlaviviridaefamily. DENV is a global public health problem with significant social and economic impacts, especially in tropical and subtropical areas. JEV is a neurotropic arbovirus endemic to east and southeast Asia. There are no U.S. FDA-approved antiviral drugs available to treat or to prevent DENV and JEV infections, leaving nearly one-third of the world’s population at risk for infection. Therefore, it is crucial to discover potent antiviral agents against these viruses. Nucleoside analogs, as a class, are widely used for the treatment of viral infections. In this study, we discovered nucleoside analogs that possess potent and selective anti-JEV and anti-DENV activities across all serotypes in cell-based assay systems. Both viruses were susceptible to sugar-substituted 2′-C-methyl analogs with either cytosine or 7-deaza-7-fluoro-adenine nucleobases. Mouse studies confirmed the anti-DENV activity of these nucleoside analogs. Molecular models were assembled for DENV serotype 2 (DENV-2) and JEV RNA-dependent RNA polymerase replication complexes bound to nucleotide inhibitors. These models show similarities between JEV and DENV-2, which recognize the same nucleotide inhibitors. Collectively, our findings provide promising compounds and a structural rationale for the development of direct-acting antiviral agents with dual activity against JEV and DENV infections.

scholarly journals Inhibition of B Virus (Macacine herpesvirus 1) by Conventional and Experimental Antiviral Compounds

2009 ◽  
Vol 54 (1) ◽  
pp. 452-459 ◽  
Author(s):  
P. W. Krug ◽  
R. F. Schinazi ◽  
J. K. Hilliard
Keyword(s):  
Antiviral Treatment ◽  
Antiviral Agents ◽  
Antiviral Drug ◽  
Nucleoside Analogs ◽  
High Morbidity ◽  
Virus Infections ◽  
Experimental Drugs ◽  
B Virus ◽  
Simplex Virus ◽  
Virus Isolates

ABSTRACT B virus infection of humans results in high morbidity and mortality in as many as 80% of identified cases. The main objective of this study was to conduct a comparative analysis of conventional and experimental antiviral drug susceptibilities of B virus isolates from multiple macaque species and zoonotically infected humans. We used a plaque reduction assay to establish the effective inhibitory doses of acyclovir, ganciclovir, and vidarabine, as well as those of a group of experimental nucleoside analogs with known anti-herpes simplex virus activity. Four of the experimental drugs tested were 10- to 100-fold more potent inhibitors of B virus replication than conventional antiviral agents. Drug efficacies were similar for multiple B virus isolates tested, with variations within 2-fold of the median effective concentration (EC50) for each drug, and each EC50 was considerably lower than those for B virus thymidine kinase (TK) mutants. We observed no differences in the viral TK amino acid sequence between B virus isolates from rhesus monkeys and those from human zoonoses. Differences in the TK protein sequence between cynomolgus and pigtail macaque B virus isolates did not affect drug sensitivity except in the case of one compound. Taken together, these data suggest that future B virus zoonoses will respond consistently to conventional antiviral treatment. Further, the considerably higher potency of FEAU (2′-fluoro-5-ethyl-Ara-U) than of conventional antiviral drugs argues for its compassionate use in advanced human B virus infections.

The past as Prelude to the Future: History, Status, and Future of Antiviral Drugs

1996 ◽  
Vol 30 (9) ◽  
pp. 967-971 ◽  
Author(s):  
Richard J Whitley
Keyword(s):  
Antiviral Therapy ◽  
English Language ◽  
Data Extraction ◽  
Antiviral Agents ◽  
Antiviral Agent ◽  
Nucleoside Analogs ◽  
Phase Iii ◽  
Clinical Value ◽  
Medline Search ◽  
Aids Epidemic

OBJECTIVE: To review the first generation of antiviral agents (e.g., idoxuridine, amantadine, vidarabine) that paralleled discovery of antineoplastic agents. DATA SOURCES: A MEDLINE search (1962 to 1996) of the English-language literature pertaining to antiviral agents was performed. DATA EXTRACTION: All articles were considered for this review. Pertinent references on antiviral therapy, as judged by the author, were selected. DATA SYNTHESIS: Acyclovir, the first second-generation antiviral agent, has a known selective mechanism of action and provides the model for development of future antiviral therapies. Despite the safety and clinical value of acyclovir, therapy does not prevent establishment of latency or decrease frequency of occurrences, resistance has been documented, and outcome is frequently poor. With the emergence of the HIV/AIDS epidemic, several antiretroviral agents have been developed and approved. However, none of the four available nucleoside analogs provides a cure. CONCLUSIONS: Viral resistance has emerged as an important component of antiviral therapy. Improved therapies for cytomegalovirus are needed. Several new therapies for herpes zoster, including prodrugs, are licensed or in Phase III clinical trials. Future directions include the use of molecular biologic techniques to identify enzymes unique to viral replication and to accelerate diagnosis of viral diseases.

Solid-phase extraction combined with radioimmunoassay for measurement of zalcitabine (2',3'-dideoxycytidine) in plasma and serum

1994 ◽  
Vol 40 (2) ◽  
pp. 211-215 ◽  
Author(s):  
W L Roberts ◽  
T J Buckley ◽  
P M Rainey ◽  
P I Jatlow
Keyword(s):  
Solid Phase Extraction ◽  
Solid Phase ◽  
Antiviral Agents ◽  
Plasma Concentrations ◽  
Cation Exchange Resin ◽  
Nucleoside Analogs ◽  
Cross Reactivity ◽  
Chromatographic Technique ◽  
Phase Extraction ◽  
Limit Of Quantitation

Abstract Of the antiviral agents that are currently in clinical use in the US for therapy for human immunodeficiency virus infections, zalcitabine (ddC) is the most potent and is effective at the lowest plasma concentrations. The two reported procedures for measuring these low concentrations involve a chromatographic technique coupled with mass spectrometry. We have developed a procedure combining solid-phase extraction with a strong cation-exchange resin and commercially available RIA reagents for the quantification of ddC in plasma or serum. The method demonstrates good linearity, specificity, and precision, with overall CVs of < 10% from 2-20 micrograms/L and 17% at 0.8 microgram/L (the lower limit of quantitation). No significant cross-reactivity with nucleoside analogs other than ddC analogs was noted. The major advantages of this assay are its efficiency and relative simplicity, which should facilitate its performance in many laboratories.

A Review of Topical Imiquimod in the Management of Basal Cell Carcinoma, Actinic Keratoses, and Other Skin Lesions

2009 ◽  
Vol 1 ◽  
pp. CMT.S1969
Author(s):  
Jubin Ryu ◽  
F. Clarissa Yang
Keyword(s):  
Basal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Basal Cell ◽  
Antiviral Agents ◽  
Nucleoside Analogs ◽  
Skin Lesions ◽  
Off Label ◽  
Trade Name ◽  
Superficial Basal Cell Carcinoma ◽  
External Genital Warts

Imiquimod (trade name Aldara™) is a small molecule of the imidazoquinoline family, a group of nucleoside analogs that were first synthesized as potential antiviral agents. It has since been discovered to activate both innate and adaptive immunity, as well as apoptosis. Clinically, it has been approved for three indications thus far: external genital warts, actinic keratosis, and superficial basal cell carcinoma. In addition to these applications, a number of off-label uses have been reported in the literature. In this review, we summarize and discuss the literature describing imiquimod's mechanism of action, its approved and off-label clinical uses, and its safety and tolerability.

scholarly journals The experience of domestic antiviral agents, and some of own approaches in the treatment of chronic hepatitis C in adults

2015 ◽  
Vol 20 (3) ◽  
pp. 4-10
Author(s):  
V. A Borisov ◽  
B. I Sanin ◽  
S. E Samsonova ◽  
E. N Arutyunyan ◽  
D. B Golubeva ◽  
...  
Keyword(s):  
Chronic Hepatitis ◽  
Hepatitis C ◽  
Chronic Hepatitis C ◽  
Gradual Increase ◽  
Antiviral Agents ◽  
Nucleoside Analogs ◽  
Antiviral Drugs ◽  
Weekly Dose ◽  
Glycyrrhizinic Acid ◽  
Cell Immunity

In the management of 148 adult patients with chronic hepatitis C (CHC) of both sexes without special selection (taken into account only absolute contraindications to its performance) there were used domestic basic antiviral drugs - BAD\ (short-living interferons (IFN) a, interferon inducers and nucleoside analogues) in parallel with additional antiviral drugs (drug glycyrrhizinic acid or amantadine) and maintenance therapy (stimulators of T-cell immunity and means of correction of side effects). Treatment was carried out in the framework of the developed complex of principles and approaches including in part, the formation of the starting average weekly dose of interferon IFN with accounting of the character of interferon status of the patient, a gradual increase in the average weekly dose of interferon IFN during the course of therapy, the delayed use of nucleoside analogs and others. As a result, against the background of a significant reduction in financial expenses and the aggressiveness of treatment the stable positive therapeutic outcome in the general population ofpatients occurred in 92.6%, with 87.2% in patients with genotype (G) 1.

scholarly journals Fruit Bromelain-Derived Peptide Potentially Restrains the Attachment of SARS-CoV-2 Variants to hACE2: A Pharmacoinformatics Approach

Molecules ◽  
2022 ◽  
Vol 27 (1) ◽  
pp. 260
Author(s):  
Trina Ekawati Tallei ◽  
Fatimawali ◽  
Ahmad Akroman Adam ◽  
Mona M. Elseehy ◽  
Ahmed M. El-Shehawi ◽  
...  
Keyword(s):  
Root Mean Square ◽  
Antiviral Agents ◽  
Md Simulations ◽  
Radius Of Gyration ◽  
Mean Square ◽  
Angiotensin Converting Enzyme 2 ◽  
In Silico Study ◽  
Mean Square Fluctuation ◽  
Binding Residues ◽  
Binding Energy Calculations

Before entering the cell, the SARS-CoV-2 spike glycoprotein receptor-binding domain (RBD) binds to the human angiotensin-converting enzyme 2 (hACE2) receptor. Hence, this RBD is a critical target for the development of antiviral agents. Recent studies have discovered that SARS-CoV-2 variants with mutations in the RBD have spread globally. The purpose of this in silico study was to determine the potential of a fruit bromelain-derived peptide. DYGAVNEVK. to inhibit the entry of various SARS-CoV-2 variants into human cells by targeting the hACE binding site within the RBD. Molecular docking analysis revealed that DYGAVNEVK interacts with several critical RBD binding residues responsible for the adhesion of the RBD to hACE2. Moreover, 100 ns MD simulations revealed stable interactions between DYGAVNEVK and RBD variants derived from the trajectory of root-mean-square deviation (RMSD), radius of gyration (Rg), and root-mean-square fluctuation (RMSF) analysis, as well as free binding energy calculations. Overall, our computational results indicate that DYGAVNEVK warrants further investigation as a candidate for preventing SARS-CoV-2 due to its interaction with the RBD of SARS-CoV-2 variants.

scholarly journals Disassembly of HIV envelope glycoprotein trimer immunogens is driven by antibodies elicited via immunization

2021 ◽  
Author(s):  
Hannah L. Turner ◽  
Raiees Andrabi ◽  
Christopher A. Cottrell ◽  
Sara T. Richey ◽  
Ge Song ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Envelope Glycoprotein ◽  
Neutralizing Antibodies ◽  
Epitope Mapping ◽  
Antibody Responses ◽  
Viral Fusion ◽  
Protein Subunit ◽  
Subunit Vaccines ◽  
Hiv Envelope ◽  
Viral Surface

AbstractRationally designed protein subunit vaccines are being developed for a variety of viruses including influenza, RSV, SARS-CoV-2 and HIV. These vaccines are based on stabilized versions of the primary targets of neutralizing antibodies on the viral surface, namely viral fusion glycoproteins. While these immunogens display the epitopes of potent neutralizing antibodies, they also present epitopes recognized by non or weakly neutralizing (“off-target”) antibodies. Using our recently developed electron microscopy epitope mapping approach, we have uncovered a phenomenon wherein off-target antibodies elicited by HIV trimer subunit vaccines cause the otherwise highly stabilized trimeric proteins to degrade into cognate protomers. Further, we show that these protomers expose an expanded suite of off-target epitopes, normally occluded inside the prefusion conformation of trimer, that subsequently elicit further off-target antibody responses. Our study provides critical insights for further improvement of HIV subunit trimer vaccines for future rounds of the iterative vaccine design process.

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