scholarly journals Discovery of a Novel Tetrapeptide against Influenza A Virus: Rational Design, Synthesis, Bioactivity Evaluation and Computational Studies

2021 ◽  
Vol 14 (10) ◽  
pp. 959
Author(s):  
Maria Carmina Scala ◽  
Mariangela Agamennone ◽  
Agostina Pietrantoni ◽  
Veronica Di Sarno ◽  
Alessia Bertamino ◽  
...  
Keyword(s):  
Influenza A ◽  
Rational Design ◽  
Respiratory Illness ◽  
New Drugs ◽  
Bovine Lactoferrin ◽  
Computational Studies ◽  
Cell Infection ◽  
Design Synthesis ◽  
Influenza Activity ◽  
Reference Peptide

Influenza is a highly contagious, acute respiratory illness, which represents one of the main health issues worldwide. Even though some antivirals are available, the alarming increase in virus strains resistant to them highlights the need to find new drugs. Previously, Superti et al. deeply investigated the mechanism of the anti-influenza virus effect of bovine lactoferrin (bLf) and the role of its tryptic fragments (the N- and C-lobes) in antiviral activity. Recently, through a truncation library, we identified the tetrapeptides, Ac-SKHS-NH2 (1) and Ac-SLDC-NH2 (2), derived from bLf C-lobe fragment 418–429, which were able to bind hemagglutinin (HA) and inhibit cell infection in a concentration range of femto- to picomolar. Starting from these results, in this work, we initiated a systematic SAR study on the peptides mentioned above, through an alanine scanning approach. We carried out binding affinity measurements by microscale thermophoresis (MST) and surface plasmon resonance (SPR), as well as hemagglutination inhibition (HI) and virus neutralization (NT) assays on synthesized peptides. Computational studies were performed to identify possible ligand–HA interactions. Results obtained led to the identification of an interesting peptide endowed with broad anti-influenza activity and able to inhibit viral infection to a greater extent of reference peptide.

scholarly journals Discovery of a Novel Tetrapeptide Against Influenza A Virus: Rational Design, Synthesis, Bioactivity Evaluation and Computational Studies

2021 ◽  
Author(s):  
Maria Carmina Scala ◽  
Mariangela Agamennone ◽  
Agostina Pietrantoni ◽  
Veronica Di Sarno ◽  
Alessia Bertamino ◽  
...  
Keyword(s):  
Influenza A ◽  
Rational Design ◽  
Respiratory Illness ◽  
New Drugs ◽  
Bovine Lactoferrin ◽  
Computational Studies ◽  
Cell Infection ◽  
Design Synthesis ◽  
Influenza Activity ◽  
Reference Peptide

Influenza is a highly contagious, acute respiratory illness, which represents one of the main health issues worldwide. Even though some antivirals are available, the alarming increase of virus strains resistant to them highlights the need to find new drugs. Previously, Superti et al. have deeper investigated the mechanism of the anti-Influenza virus effect of bovine Lactoferrin (bLf) and the role of its tryptic fragments (the N and C-lobes) in the antiviral activity. Recently, through a truncation library, we identified the tetrapeptides, SKHS (1) and SLDC (2), derived from bLf C-lobe fragment 418-429, which were able to bind hemagglutinin (HA) and inhibit cell infection in a concentration range of femto- to picomolar. Starting from these results, in this work, we initiated a systematic SAR study on the peptides mentioned above, through an Alanine scanning approach. We carried out binding affinity measurements by microscale thermophoresis (MST) and Surface Plasmon Resonance (SPR), and hemagglutination inhibition (HI) and virus neutralization (NT) assays on synthesized peptides. Computational studies were performed to identify possible lig-and-HA interactions. Results obtained led to the identification of an interesting peptide endowed with broad anti-Influenza activity and able to inhibit viral infection to a greater extent of reference peptide.

Antiviral Treatments for Influenza

2021 ◽  
Vol 42 (06) ◽  
pp. 859-872
Author(s):  
Emanuele Palomba ◽  
Valeria Castelli ◽  
Giulia Renisi ◽  
Alessandra Bandera ◽  
Andrea Lombardi ◽  
...  
Keyword(s):  
Influenza A ◽  
Respiratory Illness ◽  
Chronic Respiratory Disease ◽  
New Drugs ◽  
Special Populations ◽  
Efficacy And Safety ◽  
The Past ◽  
Dependent Endonuclease ◽  
History Of ◽  
Seasonal Epidemics

AbstractInfluenza is an acute respiratory illness caused by the influenza A, B, and C viruses. It can occur in local outbreaks or seasonal epidemics, with possibility to spread worldwide in a pandemic when a novel strain with significant antigenic differences emerges. During the past years, several new drugs have become available, with different accessibility related to specific countries' approval. We have conducted a review of literature, analyzing the most recent data on efficacy and safety of drugs currently available to treat influenza, with a particular attention toward special populations. Efficacy and safety profile of neuraminidase inhibitors (oseltamivir, zanamivir, laninamivir, peramivir) and recently approved cap-dependent endonuclease inhibitor baloxavir marboxil are reported in literature, but still little information is available about special populations such as critically ill patients and patients with a history of chronic respiratory disease. Moreover, the emergence of strains with reduced or no susceptibility to current drugs is a matter of concern, suggesting the need of constant monitoring of viral variants.

Structure-based identification of small molecules against influenza A virus endonuclease: an in silico and in vitro approach

2020 ◽  
Vol 78 (4) ◽  
Author(s):  
Sai Disha K. ◽  
Rashmi Puranik ◽  
Sudheesh N. ◽  
Kavitha K. ◽  
Fajeelath Fathima ◽  
...  
Keyword(s):  
Small Molecules ◽  
Influenza A Virus ◽  
Influenza A ◽  
Protein A ◽  
Antiviral Drug ◽  
Respiratory Illness ◽  
Influenza Viruses ◽  
Influenza Activity ◽  
Viral Target

ABSTRACT Influenza viruses are known to cause acute respiratory illness, sometimes leading to high mortality rates. Though there are approved influenza antivirals available, their efficacy has reduced over time, due to the drug resistance crisis. There is a perpetual need for newer and better drugs. Drug screening based on the interaction dynamics with different viral target proteins has been a preferred approach in the antiviral drug discovery process. In this study, the FDA approved drug database was virtually screened with the help of Schrödinger software, to select small molecules exhibiting best interactions with the influenza A virus endonuclease protein. A detailed cytotoxicity profiling was carried out for the two selected compounds, cefepime and dolutegravir, followed by in vitro anti-influenza screening using plaque reduction assay. Cefepime showed no cytotoxicity up to 200 μM, while dolutegravir was non-toxic up to 100 μM in Madin–Darby canine kidney cells. The compounds did not show any reduction in viral plaque numbers indicating no anti-influenza activity. An inefficiency in the translation of the molecular interactions into antiviral activity does not necessarily mean that the molecules were inactive. Nevertheless, testing the molecules for endonuclease inhibition per se can be considered a worthwhile approach.

The Discovery and Development of Oxalamide and Pyrrole Small Molecule Inhibitors of gp120 and HIV Entry - A Review

2019 ◽  
Vol 19 (18) ◽  
pp. 1650-1675 ◽  
Author(s):  
Damoder Reddy Motati ◽  
Dilipkumar Uredi ◽  
E. Blake Watkins
Keyword(s):  
Small Molecule ◽  
Viral Entry ◽  
Biological Evaluation ◽  
New Drugs ◽  
Design Synthesis ◽  
Mortality And Morbidity ◽  
Glycoprotein Gp120 ◽  
Hiv Entry ◽  
Immunodeficiency Syndrome ◽  
Hiv 1

Human immunodeficiency virus type-1 (HIV-1) is the causative agent responsible for the acquired immunodeficiency syndrome (AIDS) pandemic. More than 60 million infections and 25 million deaths have occurred since AIDS was first identified in the early 1980s. Advances in available therapeutics, in particular combination antiretroviral therapy, have significantly improved the treatment of HIV infection and have facilitated the shift from high mortality and morbidity to that of a manageable chronic disease. Unfortunately, none of the currently available drugs are curative of HIV. To deal with the rapid emergence of drug resistance, off-target effects, and the overall difficulty of eradicating the virus, an urgent need exists to develop new drugs, especially against targets critically important for the HIV-1 life cycle. Viral entry, which involves the interaction of the surface envelope glycoprotein, gp120, with the cellular receptor, CD4, is the first step of HIV-1 infection. Gp120 has been validated as an attractive target for anti-HIV-1 drug design or novel HIV detection tools. Several small molecule gp120 antagonists are currently under investigation as potential entry inhibitors. Pyrrole, piperazine, triazole, pyrazolinone, oxalamide, and piperidine derivatives, among others, have been investigated as gp120 antagonist candidates. Herein, we discuss the current state of research with respect to the design, synthesis and biological evaluation of oxalamide derivatives and five-membered heterocycles, namely, the pyrrole-containing small molecule as inhibitors of gp120 and HIV entry.

The design, synthesis, pharmacokinetic and pharmacodynamic evaluation of acyloxyalkyl-substituted T705 prodrugs

2019 ◽  
Vol 15 ◽  
Author(s):  
Xingzhou Li ◽  
Tianhong Zhang ◽  
Wu Zhong
Keyword(s):  
Plasma Concentration ◽  
Development Strategy ◽  
Parent Compound ◽  
Systemic Exposure ◽  
Parent Drug ◽  
New Drugs ◽  
Structure Modification ◽  
Design Synthesis ◽  
Pharmacokinetic Properties

Background: The pharmacokinetic properties of T705 are not optimal for the development of new drugs. Objective: To improve the pharmacokinetic properties of T-705, structure modification of T-705 was conducted using a prodrug strategy. Method: The acidic amide H atom (N4-H) of T705 was attempted to be replaced with acyloxyalkyl groups following the prodrugs development strategy for carboxylic acids, and the resulting compounds were investigated whether could work as prodrugs and contribute to improving the pharmacokinetic properties of the parent compound T705 in vivo. Results: 4-acyloxyalkyl-T705 (4a–e), did act as prodrugs in vivo. 4-iso-butyryloxymethyl-T705 (4a) and 4-acetoxymethyl-T705 (4b) could significantly improve the plasma concentration and systemic exposure for T705, compound 4a displayed non inferior anti-influenza activities, compared with its parent drug T705. Conclusion: Our prodrugs development strategy for T705 is feasible, which may serves as a reference to prodrugs development of similar heterocyclic amides compounds.

Design, Synthesis, Evaluation and Computational Studies of Nipecotic Acid-Acetonaphthone Hybrids as Potential Antiepileptic Agents

2018 ◽  
Vol 14 (4) ◽  
pp. 409-426 ◽  
Author(s):  
Ankit Seth ◽  
Piyoosh A. Sharma ◽  
Avanish Tripathi ◽  
Priyanka K. Choubey ◽  
Pavan Srivastava ◽  
...  
Keyword(s):  
Computational Studies ◽  
Nipecotic Acid ◽  
Design Synthesis ◽  
Antiepileptic Agents

scholarly journals The Effects of Social Distancing Policies on non-SARS-CoV-2 Respiratory Pathogens

2021 ◽  
Author(s):  
Jeff Nawrocki ◽  
Katherine Olin ◽  
Martin C Holdrege ◽  
Joel Hartsell ◽  
Lindsay Meyers ◽  
...  
Keyword(s):  
Public Health ◽  
Influenza A ◽  
Detection Rate ◽  
Respiratory Illness ◽  
Respiratory Pathogens ◽  
Public Health Response ◽  
Mixed Effect ◽  
Detection Rates ◽  
Social Distancing ◽  
The Impact

Abstract Background The initial focus of the US public health response to COVID-19 was the implementation of numerous social distancing policies. While COVID-19 was the impetus for imposing these policies, it is not the only respiratory disease affected by their implementation. This study aimed to assess the impact of social distancing policies on non-SARS-CoV-2 respiratory pathogens typically circulating across multiple US states. Methods Linear mixed-effect models were implemented to explore the effects of five social distancing policies on non-SARS-CoV-2 respiratory pathogens across nine states from January 1 through May 1, 2020. The observed 2020 pathogen detection rates were compared week-by-week to historical rates to determine when the detection rates were different. Results Model results indicate that several social distancing policies were associated with a reduction in total detection rate, by nearly 15%. Policies were associated with decreases in pathogen circulation of human rhinovirus/enterovirus and human metapneumovirus, as well as influenza A, which typically decrease after winter. Parainfluenza viruses failed to circulate at historical levels during the spring. Total detection rate in April 2020 was 35% less than historical average. Many of the pathogens driving this difference fell below historical detection rate ranges within two weeks of initial policy implementation. Conclusion This analysis investigated the effect of multiple social distancing policies implemented to reduce transmission of SARS-CoV-2 on non-SARS-CoV-2 respiratory pathogens. These findings suggest that social distancing policies may be used as an impactful public health tool to reduce communicable respiratory illness.

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