scholarly journals Recent discoveries of influenza A drug target sites to combat virus replication

2016 ◽  
Vol 44 (3) ◽  
pp. 932-936 ◽  
Author(s):  
Hershna Patel ◽  
Andreas Kukol
Keyword(s):  
Drug Discovery ◽  
Virus Replication ◽  
Binding Sites ◽  
Drug Target ◽  
Influenza A ◽  
Antiviral Drug ◽  
Virus Transmission ◽  
Computational Tools ◽  
Sequence Variations ◽  
Target Sites

Sequence variations in the binding sites of influenza A proteins are known to limit the effectiveness of current antiviral drugs. Clinically, this leads to increased rates of virus transmission and pathogenicity. Potential influenza A inhibitors are continually being discovered as a result of high-throughput cell based screening studies, whereas the application of computational tools to aid drug discovery has further increased the number of predicted inhibitors reported. This review brings together the aspects that relate to the identification of influenza A drug target sites and the findings from recent antiviral drug discovery strategies.

Chios mastic gum inhibits influenza A virus replication and viral pathogenicity

2021 ◽  
Author(s):  
Dong-In Kim ◽  
Yong-Bin Cho ◽  
Younghyun Lim ◽  
So-Hee Hong ◽  
Bumsuk Hahm ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Virus Replication ◽  
Influenza A ◽  
Bacterial Infections ◽  
Early Stage ◽  
Antiviral Drug ◽  
Virus Infectivity ◽  
Viral Attachment ◽  
Cellular Processes ◽  
Chios Mastic Gum

Chios mastic gum (CMG), a resin of the mastic tree (Pistacia lentiscus var. chia), has been used to treat multiple disorders caused by gastrointestinal malfunctions and bacterial infections for more than 2500 years. However, little is known about CMG’s antiviral activity. CMG is known to influence multiple cellular processes such as cell proliferation, differentiation and apoptosis. As virus replication is largely dependent on the host cellular metabolism, it is conceivable that CMG regulates virus infectivity. Therefore, in this study, we evaluated CMG’s potential as an antiviral drug to treat influenza A virus (IAV) infection. CMG treatment dramatically reduced the cytopathogenic effect and production of RNAs, proteins and infectious particles of IAV. Interestingly, CMG interfered with the early stage of the virus life cycle after viral attachment. Importantly, the administration of CMG greatly ameliorated morbidity and mortality in IAV-infected mice. The results suggest that CMG displays a potent anti-IAV activity by blocking the early stage of viral replication. Thus, mastic gum could be exploited as a novel therapeutic agent against IAV infection.

scholarly journals A Dual Controllability Analysis of Influenza Virus-Host Protein-Protein Interaction Networks for Antiviral Drug Target Discovery

2018 ◽  
Author(s):  
Emily E. Ackerman ◽  
John F. Alcorn ◽  
Takeshi Hase ◽  
Jason E. Shoemaker
Keyword(s):  
Influenza Virus ◽  
Protein Interaction ◽  
Drug Target ◽  
Influenza A ◽  
Antiviral Drug ◽  
Host Factors ◽  
Host Protein ◽  
Drug Target Discovery ◽  
Protein Protein Interaction ◽  
Protein Protein Interaction Networks

ABSTRACTHost factors of influenza virus replication are often found in key topological positions within protein-protein interaction networks. This work explores how protein states can be manipulated through controllability analysis: the determination of the minimum manipulation needed to drive the cell system to any desired state. Here, we complete a two-part controllability analysis of two protein networks: a host network representing the healthy cell state and an influenza A virus-host network representing the infected cell state. This knowledge can be utilized to understand disease dynamics and isolate proteins for study as drug target candidates. Both topological and controllability analyses provide evidence of wide-reaching network effects stemming from the addition of viral-host protein interactions. Virus interacting and driver host proteins are significant both topologically and in controllability, therefore playing important roles in cell behavior during infection. 24 proteins are identified as holding regulatory roles specific to the infected cell by measures of topology, controllability, and functional role. These proteins are recommended for further study as potential antiviral drug targets.ImportanceSeasonal outbreaks of influenza A virus are a major cause of illness and death around the world each year, with a constant threat of pandemic infection. Even so, the FDA has only approved four treatments, two of which are unsuited for at risk groups such as children and those with breathing complications. This research aims to increase the efficiency of antiviral drug target discovery using existing protein-protein interaction data and network analysis methods. Controllability analyses identify key regulating host factors of the infected cell’s progression, findings which are supported by biological context. These results are beneficial to future studies of influenza virus, both experimental and computational.

A Novel Evolutionary Approach Provides Hope for Limiting Future Drug Resistance in Malaria

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 420-420
Author(s):  
Theresa L. Coetzer ◽  
Kubendran Naidoo ◽  
Pierre Durand
Keyword(s):  
Drug Resistance ◽  
Drug Discovery ◽  
Dihydrofolate Reductase ◽  
Drug Target ◽  
Purifying Selection ◽  
Evolutionary Change ◽  
Potential Drug Target ◽  
Potential Drug ◽  
Novel Approach ◽  
Target Sites

Abstract Malaria continues to be the most lethal protozoan disease of humans and the pathogenesis is fundamentally associated with the infection and hemolysis of red blood cells. Due to the emergence of resistance to most current drugs, there is an urgent need to develop a new generation of anti-parasitic agents. Drug development programs are expensive, long-term endeavors with numerous bottlenecks that exhibit a high rate of attrition. A major concern following the scientific and financial investment in drug discovery is the emergence of drug resistance. This is a well documented problem in malaria, and may be exceedingly rapid, classically demonstrated by pyrimethamine-resistant Plasmodium falciparum malaria. Strategies therefore that identify the most suitable drug target sites to minimize resistance are of major interest. In this study, a novel approach to select such sites based on the evolutionary rate of change is described, using the P. falciparum glycerol kinase (PfGK) as an example. The ratio of non-synonymous (dN) to synonymous (dS) nucleotide substitutions is defined as omega and was used to identify the patterns of evolutionary change at individual codons in the parasite and orthologous human (HsGK) coding sequences. The omega value of a particular codon reflects the evolutionary forces acting on the corresponding amino acid in the protein sequence. Natural selection will retain mutations that are beneficial to the organism and eliminate those that are detrimental. Omega values typically fall into three categories: positive selection (omega>1.0), neutral (omega=1.0), or purifying selection (omega<1.0). In this study, we quantified the relative intensity of selection and introduced the category of extreme purifying selection (omega≤0.1) to identify sites under the most severe evolutionary constraints. We have termed this novel approach to drug target selection “evolutionary patterning” (EP). EP describes the pattern of evolutionary change across a coding sequence, thereby identifying residues that make the most (omega<0.1) and least (omega>1.0) suitable drug target sites based on their potential to produce viable mutations. The EP approach was validated using the P. falciparum dihydrofolate reductase gene. Pyrimethamine targets the dihydrofolate reductase enzyme and five mutations conferring drug resistance have been identified. We hypothesized that none of these mutations would be under extreme purifying selection and our EP investigation confirmed this. EP analysis was thus applied to PfGK, which could be a potential novel drug target. PfGK is annotated as a putative glycerol kinase in the PlasmoDB database and to confirm this predicted function, the full length gene of 1506bp was cloned into a pGEX-4T2 expression vector, the recombinant GST-fusion protein was expressed in E coli and an in vitro assay showed that the enzyme was active and could phosphorylate glycerol. Glycerol-3-phosphate is a multifunctional metabolite that is essential for glycerolipid synthesis and also feeds into glycolysis, highlighting its essential role in parasite metabolism. EP analysis of the PfGK and HsGK genes was conducted separately as part of protozoan and metazoan clades, respectively, and key differences in the evolutionary patterns of the two molecules were identified. These differences were exploited to target the parasite selectively and six potential drug target sites were chosen, which contained residues under extreme purifying selection. To assess the functional and structural significance of these regions, as well as their accessibility to potential therapeutic molecules, they were mapped onto a 3D model of PfGK. This analysis ruled out three of the potential sites, since they were either not essential for enzyme activity or were embedded in the hydrophobic core of the enzyme. In collaboration with medicinal chemists the remaining three potential drug target sites will be used for in silico drug design and docking studies. The strategy of EP and refinement with structural modeling is generic in nature and will limit the development of drug resistance. This represents a significant advance for drug discovery programs in malaria and other infectious diseases.

scholarly journals The SKI complex is a broad-spectrum, host-directed antiviral drug target for coronaviruses, influenza, and filoviruses

2020 ◽  
Vol 117 (48) ◽  
pp. 30687-30698
Author(s):  
Stuart Weston ◽  
Lauren Baracco ◽  
Chloe Keller ◽  
Krystal Matthews ◽  
Marisa E. McGrath ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Drug Target ◽  
Influenza A ◽  
Genetic Interaction ◽  
Antiviral Drug ◽  
Binding Pocket ◽  
Potential Host ◽  
Lead Compounds ◽  
Chemical Structures ◽  
In Silico Modeling

The SARS-CoV-2 pandemic has made it clear that we have a desperate need for antivirals. We present work that the mammalian SKI complex is a broad-spectrum, host-directed, antiviral drug target. Yeast suppressor screening was utilized to find a functional genetic interaction between proteins from influenza A virus (IAV) and Middle East respiratory syndrome coronavirus (MERS-CoV) with eukaryotic proteins that may be potential host factors involved in replication. This screening identified the SKI complex as a potential host factor for both viruses. In mammalian systems siRNA-mediated knockdown of SKI genes inhibited replication of IAV and MERS-CoV. In silico modeling and database screening identified a binding pocket on the SKI complex and compounds predicted to bind. Experimental assays of those compounds identified three chemical structures that were antiviral against IAV and MERS-CoV along with the filoviruses Ebola and Marburg and two further coronaviruses, SARS-CoV and SARS-CoV-2. The mechanism of antiviral activity is through inhibition of viral RNA production. This work defines the mammalian SKI complex as a broad-spectrum antiviral drug target and identifies lead compounds for further development.

scholarly journals Rationalizing Viral Drug Target Identification Using Computational Approaches : The SARS-CoV-2 Spike Glycoprotein S Case Study

2020 ◽  
Author(s):  
Petr Popov ◽  
Pavel Buslaev ◽  
Igor Kozlovskii ◽  
Mark Zaretskii ◽  
Dmitry Karlov ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Binding Site ◽  
Binding Sites ◽  
Drug Target ◽  
Conformational Transition ◽  
Target Identification ◽  
Drug Binding ◽  
Spike Glycoprotein ◽  
Important Amino Acid ◽  
Drug Target Identification

<div><div><div><p>COVID-19 emphasized the need for fast reaction tools to fight global biological threats such as viruses. Rapid drug discovery is one of the strategies for efficient social response. The success of a drug discovery campaign critically depends on the selected drug target, and the wrong target nullifies all the efforts to develop a drug. Viral drug target identification is a challenging problem, and computational methods can reduce the number of candidate targets. Here we present a structure-based approach to identify vulnerable regions in viral proteins that comprise drug binding sites. To detect promising binding sites, we take into account protein dynamics, accessibility, and mutability of the binding site, coupled with the putative mechanism of action of a drug. Applying to the SARS-CoV-2 Spike Glycoprotein S, we observed conformation- and oligomer-specific glycan-free binding site that is proximal to the receptor binding domain and comprises topologically important amino acid residues. Molecular dynamics simulations of Spike in complex with drug-like molecules docked into the binding sites revealed shifted equilibrium towards the inactive conformation compared to the ligand-free simulations. Small molecules targeting this binding site could prevent the closed-to-open conformational transition of the Spike protein, thus, allosterically inhibit the interaction with the human angiotensin-converting enzyme 2 receptor.</p></div></div></div>

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