scholarly journals Broad-spectrum mono- and combinational drug therapies for global viral pandemic preparedness

2022 ◽  
Author(s):  
Aleksandr Ianevski ◽  
Rouan Yao ◽  
Ronja Meyer Simonsen ◽  
Vegard Myhre ◽  
Erlend Ravlo ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Scoring Systems ◽  
Mechanisms Of Action ◽  
Pandemic Preparedness ◽  
Host Interactions ◽  
Antiviral Therapies ◽  
New Strategy ◽  
Life Threatening ◽  
Immunomodulatory Properties ◽  
Combinational Therapies

Broadly effective antiviral therapies must be developed to be ready for clinical trials, which should begin soon after the emergence of new life-threatening viruses. Here, we pave the way towards this goal by analyzing conserved druggable virus-host interactions, mechanisms of action and immunomodulatory properties of broad-spectrum antivirals (BSAs), routes of BSA delivery, and BSA interactions with other antivirals. Based on the analysis we developed scoring systems, which allowed us to predict novel BSAs and BSA-containing drug combinations (BCCs). Thus, we have developed a new strategy to broaden the spectrum of BSA indications and predict novel mono- and combinational therapies that can help better prepare for imminent future viral outbreaks.

scholarly journals Modulation of Endosome Function, Vesicle Trafficking and Autophagy by Human Herpesviruses

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 542
Author(s):  
Eduardo I. Tognarelli ◽  
Antonia Reyes ◽  
Nicolás Corrales ◽  
Leandro J. Carreño ◽  
Susan M. Bueno ◽  
...  
Keyword(s):  
Membrane Trafficking ◽  
Viral Gene ◽  
Barr Virus ◽  
Cellular Processes ◽  
Antiviral Therapies ◽  
Host Determinants ◽  
Viral Particles ◽  
Life Threatening ◽  
Epstein Barr ◽  
Human Herpesviruses

Human herpesviruses are a ubiquitous family of viruses that infect individuals of all ages and are present at a high prevalence worldwide. Herpesviruses are responsible for a broad spectrum of diseases, ranging from skin and mucosal lesions to blindness and life-threatening encephalitis, and some of them, such as Kaposi’s sarcoma-associated herpesvirus (KSHV) and Epstein–Barr virus (EBV), are known to be oncogenic. Furthermore, recent studies suggest that some herpesviruses may be associated with developing neurodegenerative diseases. These viruses can establish lifelong infections in the host and remain in a latent state with periodic reactivations. To achieve infection and yield new infectious viral particles, these viruses require and interact with molecular host determinants for supporting their replication and spread. Important sets of cellular factors involved in the lifecycle of herpesviruses are those participating in intracellular membrane trafficking pathways, as well as autophagic-based organelle recycling processes. These cellular processes are required by these viruses for cell entry and exit steps. Here, we review and discuss recent findings related to how herpesviruses exploit vesicular trafficking and autophagy components by using both host and viral gene products to promote the import and export of infectious viral particles from and to the extracellular environment. Understanding how herpesviruses modulate autophagy, endolysosomal and secretory pathways, as well as other prominent trafficking vesicles within the cell, could enable the engineering of novel antiviral therapies to treat these viruses and counteract their negative health effects.

A novel tricationic fullerene C60 as broad-spectrum antimicrobial photosensitizer: mechanisms of action and potentiation with potassium iodide

2021 ◽  
Vol 20 (3) ◽  
pp. 327-341
Author(s):  
Maximiliano L. Agazzi ◽  
Javier E. Durantini ◽  
Ezequiel D. Quiroga ◽  
M. Gabriela Alvarez ◽  
Edgardo N. Durantini
Keyword(s):  
Potassium Iodide ◽  
Broad Spectrum ◽  
Mechanisms Of Action ◽  
Fullerene C60

scholarly journals Broad-Spectrum Antiviral Strategies and Nucleoside Analogues

Viruses ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 667
Author(s):  
Robert J. Geraghty ◽  
Matthew T. Aliota ◽  
Laurent F. Bonnac
Keyword(s):  
Public Health ◽  
Severe Acute Respiratory Syndrome ◽  
Broad Spectrum ◽  
Vaccine Development ◽  
Fast Response ◽  
Mechanisms Of Action ◽  
Public Health Emergency ◽  
Nucleoside Analogues ◽  
The Family ◽  
Antiviral Nucleoside

The emergence or re-emergence of viruses with epidemic and/or pandemic potential, such as Ebola, Zika, Middle East Respiratory Syndrome (MERS-CoV), Severe Acute Respiratory Syndrome Coronavirus 1 and 2 (SARS and SARS-CoV-2) viruses, or new strains of influenza represents significant human health threats due to the absence of available treatments. Vaccines represent a key answer to control these viruses. However, in the case of a public health emergency, vaccine development, safety, and partial efficacy concerns may hinder their prompt deployment. Thus, developing broad-spectrum antiviral molecules for a fast response is essential to face an outbreak crisis as well as for bioweapon countermeasures. So far, broad-spectrum antivirals include two main categories: the family of drugs targeting the host-cell machinery essential for virus infection and replication, and the family of drugs directly targeting viruses. Among the molecules directly targeting viruses, nucleoside analogues form an essential class of broad-spectrum antiviral drugs. In this review, we will discuss the interest for broad-spectrum antiviral strategies and their limitations, with an emphasis on virus-targeted, broad-spectrum, antiviral nucleoside analogues and their mechanisms of action.

scholarly journals Limosilactobacillus fermentum CECT5716: Mechanisms and Therapeutic Insights

Nutrients ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 1016
Author(s):  
María Jesús Rodríguez-Sojo ◽  
Antonio Jesús Ruiz-Malagón ◽  
María Elena Rodríguez-Cabezas ◽  
Julio Gálvez ◽  
Alba Rodríguez-Nogales
Keyword(s):  
Competitive Exclusion ◽  
Intestinal Barrier ◽  
Mechanisms Of Action ◽  
Intestinal Barrier Function ◽  
Therapeutic Approaches ◽  
Beneficial Effects ◽  
Host Health ◽  
Inflammatory Processes ◽  
Immunomodulatory Properties ◽  
Immunological Alterations

Probiotics microorganisms exert their health-associated activities through some of the following general actions: competitive exclusion, enhancement of intestinal barrier function, production of bacteriocins, improvement of altered microbiota, and modulation of the immune response. Among them, Limosilactobacillus fermentum CECT5716 has become one of the most promising probiotics and it has been described to possess potential beneficial effects on inflammatory processes and immunological alterations. Different studies, preclinical and clinical trials, have evidenced its anti-inflammatory and immunomodulatory properties and elucidated the precise mechanisms of action involved in its beneficial effects. Therefore, the aim of this review is to provide an updated overview of the effect on host health, mechanisms, and future therapeutic approaches.

scholarly journals In VitroAssessment of Combinations of Enterovirus Inhibitors against Enterovirus 71

2016 ◽  
Vol 60 (9) ◽  
pp. 5357-5367 ◽  
Author(s):  
Yizhuo Wang ◽  
Guiming Li ◽  
Shilin Yuan ◽  
Qianqian Gao ◽  
Ke Lan ◽  
...  
Keyword(s):  
Infectious Clone ◽  
Enterovirus 71 ◽  
Foot And Mouth Disease ◽  
Antiviral Effect ◽  
Mechanisms Of Action ◽  
Rational Basis ◽  
Inhibitory Mechanism ◽  
Antiviral Therapies ◽  
Resistant Phenotype ◽  
Combination Regimens

ABSTRACTEnterovirus 71 (EV-A71) is a major causative pathogen of hand, foot, and mouth disease (HFMD) epidemics. No antiviral therapies are currently available for treating EV-A71 infections. Here, we selected five reported enterovirus inhibitors (suramin, itraconazole [ITZ], GW5074, rupintrivir, and favipiravir) with different mechanisms of action to test their abilities to inhibit EV-A71 replication alone and in combination. All selected compounds have anti-EV-A71 activities in cell culture. The combination of rupintrivir and ITZ or favipiravir was synergistic, while the combination of rupintrivir and suramin was additive. The combination of suramin and favipiravir exerted a strong synergistic antiviral effect. The observed synergy was not due to cytotoxicity, as there was no significant increase in cytotoxicity when compounds were used in combinations at the tested doses. To investigate the potential inhibitory mechanism of favipiravir against enterovirus, two favipiravir-resistant EV-A71 variants were independently selected, and both of them carried an S121N mutation in the finger subdomain of the 3D polymerase. Reverse engineering of this 3D S121N mutation into an infectious clone of EV-A71 confirmed the resistant phenotype. Moreover, viruses resistant to ITZ or favipiravir remained susceptible to other inhibitors. Most notably, combined with ITZ, rupintrivir prevented the development of ITZ-resistant variants. Taken together, these results provide a rational basis for the design of combination regimens for use in the treatment of EV-A71 infections.

Anti-Malarial Drug Resistance

2022 ◽  
pp. 233-250
Author(s):  
Manish Kumar Dwivedi ◽  
Prashant Kumar Singh
Keyword(s):  
Natural Products ◽  
Protozoan Parasite ◽  
Mechanisms Of Action ◽  
New Drugs ◽  
Efficacy And Safety ◽  
Infected Female ◽  
Traditional Medicines ◽  
Anopheles Mosquitoes ◽  
Synthetic Drugs ◽  
Life Threatening

Malaria is a life-threatening infectious disease caused by a protozoan parasite of the genus Plasmodium. It is transmitted through the bites of infected female Anopheles mosquitoes. The global burden is estimated to be around 219 million cases in 87 countries. Natural compounds have been used primarily in the traditional medicine for thousands of years. For the treatment of malaria, natural products were used until the development of synthetic drugs, and most of the currently available anti-malarial drugs have been derived based on the compounds from these traditional medicinal plants. The current chapter tries to briefly indicate the emerging resistance against anti-malarial drugs and to discuss the recent research on natural products that have been evaluated for anti-malarial activity. Rigorous evaluation of the efficacy and safety of traditional medicines is required along with identification of active constituents in order to develop new drugs with novel mechanisms of action.

Assessment and care of the patient with sepsis

2020 ◽  
pp. 225-257
Author(s):  
Kevin Barrett
Keyword(s):  
Septic Shock ◽  
Early Recognition ◽  
Scoring Systems ◽  
Cardiovascular Responses ◽  
Physiological Changes ◽  
Assessment Framework ◽  
Threatening Condition ◽  
Life Threatening ◽  
Support Mechanisms ◽  
Sepsis And Septic Shock

There has been considerable recent focus on sepsis in both the clinical arena and within the general public to raise awareness of the importance of early recognition of this potentially life-threatening condition. The early recognition of sepsis by ward nurses can both reduce progression of this lethal disease and improve survival for patients in hospital. This chapter focuses on definitions of sepsis and septic shock, physiological changes associated with inflammatory and cardiovascular responses to sepsis, and a clinical assessment framework to guide practice. There is also a discussion of the use of scoring systems and how to escalate support mechanisms for patients with sepsis and septic shock.

Hypotension

2018 ◽  
pp. 163-167
Author(s):  
Angela Creditt
Keyword(s):  
Septic Shock ◽  
Severe Sepsis ◽  
Organ Failure ◽  
Broad Spectrum ◽  
Signs And Symptoms ◽  
Intravenous Fluids ◽  
Key Points ◽  
Life Threatening ◽  
New Guidelines ◽  
Sepsis And Septic Shock

Sepsis is a complex and potentially life-threatening sequela of infection that commonly occurs and can be difficult to identify. If unrecognized or undertreated, sepsis can progress to severe sepsis, septic shock, characterized by hypotension and multisystem organ failure, and ultimately death. This case illustrates classic signs and symptoms of sepsis and septic shock in a postoperative patient. Recognizing these symptoms, rapidly initiating resuscitation with intravenous fluids and broad-spectrum antibiotics and aggressive management of these patients is imperative to prevent further decompensation. In 2017, the Surviving Sepsis campaign published new guidelines to assist with the management of patients with sepsis and septic shock. Key points from these guidelines will be highlighted within this case.

Apoptosis and autophagy as a turning point in viral–host interactions: the case of human norovirus and its surrogates

2020 ◽  
Author(s):  
Sean Kennedy ◽  
Mélanie M Leroux ◽  
Alexis Simons ◽  
Brice Malve ◽  
Marc Devocelle ◽  
...  
Keyword(s):  
Viral Entry ◽  
Turning Point ◽  
Infection Process ◽  
Host Interactions ◽  
Antiviral Therapies ◽  
Leading Role ◽  
Host Interaction ◽  
Major Response ◽  
Causes Of Disease ◽  
Viral Host Interactions

Human gastroenteritis viruses are amid the major causes of disease worldwide, responsible for more than 2 million deaths per year. Human noroviruses play a leading role in the gastroenteritis outbreaks and the continuous emergence of new strains contributes to the significant morbidity and mortality. Many aspects of the viral entry and infection process remain unclear, including the major response of the host cell to the virus, which is the trigger of several programmed cell death related mechanisms. In this review, we assessed apoptosis and autophagy at various stages in the infection process to provide better understanding of the viral–host interaction. This brings us closer to fully understanding how noroviruses work, thus allowing the development of specific antiviral therapies.

scholarly journals Designed Antimicrobial Peptides Against Trauma-Related Cutaneous Invasive Fungal Wound Infections

2020 ◽  
Vol 6 (3) ◽  
pp. 184
Author(s):  
Kathryn W. Woodburn ◽  
Jesse M. Jaynes ◽  
L. Edward Clemens
Keyword(s):  
Antimicrobial Peptides ◽  
Broad Spectrum ◽  
Clinical Care ◽  
Structural Analog ◽  
Wound Infections ◽  
First Line ◽  
Empiric Treatment ◽  
Patients At Risk ◽  
Life Threatening ◽  
Traumatic Wound

Cutaneous invasive fungal wound infections after life-threatening dismounted complex blast injury (DCBI) and natural disasters complicate clinical care. These wounds often require aggressive repeated surgical debridement, can result in amputations and hemipelvectomies and have a 38% mortality rate. Given the substantial morbidity associated with cutaneous fungal wound infections, patients at risk need immediate empiric treatment mandating the use of rapidly acting broad-spectrum antimicrobials, acting on both fungi and bacteria, that are also effective against biofilm and can be administered topically. Designed antimicrobial peptides (dAMPs) are engineered analogues of innate antimicrobial peptides which provide the first line of defense against invading pathogens. The antifungal and antibacterial effect and mammalian cytotoxicity of seven innovative dAMPs, created by iterative structural analog revisions and physicochemical and functional testing were investigated. The dAMPs possess broad-spectrum antifungal activity, in addition to being effective against Gram-negative and Gram-positive bacteria, which is crucial as many wounds are polymicrobial and require immediate empiric treatment. Three of the most potent dAMPs—RP504, RP556 and RP557—possess limited mammalian cytotoxicity following 8 h incubation. If these encouraging broad-spectrum antimicrobial and rapid acting results are translated clinically, these novel dAMPs may become a first line empiric topical treatment for traumatic wound injuries.

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