Targeting Viral Surface Proteins through Structure-Based Design

The emergence of novel viral infections of zoonotic origin and mutations of existing human pathogenic viruses represent a serious concern for public health. It warrants the establishment of better interventions and protective therapies to combat the virus and prevent its spread. Surface glycoproteins catalyzing the fusion of viral particles and host cells have proven to be an excellent target for antivirals as well as vaccines. This review focuses on recent advances for computational structure-based design of antivirals and vaccines targeting viral fusion machinery to control seasonal and emerging respiratory viruses.

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The Use of Lectins as Tools to Combat SARS-CoV-2

Current Pharmaceutical Design ◽

10.2174/1381612827666210830094743 ◽

2021 ◽

Vol 27 ◽

Author(s):

Daniela Martinez ◽

Diego Amaral ◽

David Markovitz ◽

Luciano Pinto

Keyword(s):

Viral Infection ◽

Host Cells ◽

Viral Fusion ◽

Cell Receptors ◽

First Case ◽

Mannose Binding ◽

New Treatments ◽

Viral Surface

Background: in december 2019, china announced the first case of an infection caused by an, until then, unknown virus: sars-cov-2. since then, researchers have been looking for viable alternatives for the treatment and/or cure of viral infection. among the possible complementary solutions are lectins, and proteins that are reversibly bound to different carbohydrates. the spike protein, present on the viral surface, can interact with different cell receptors: ace2, cd147, and dc-signr. since lectins have an affinity for different carbohydrates, the binding with the glycosylated cell receptors represents a possibility of preventing the virus from binding to the receptors of host cells. Objective: in this review we discuss the main lectins that are possible candidates for use in the treatment of covid-19, highlighting those that have already demonstrated antiviral activity in vivo and in vitro, including mannose-binding lectin, griffithsin, banlec, and others. we also aim to discuss the possible mechanism of action of lectins, which appears to occur through the mediation of viral fusion in host cells, by binding of lectins to glycosylated receptors found in human cells and/or binding of these proteins with the spike glycoprotein, present in virus surface.moreover, we also discuss the use of lectins in clinical practice. Conclusion: Even with the development of effective vaccines, new cases of viral infection with the same virus, or new outbreaks with different viruses can occur; so, the development of new treatments should not be discarded. moreover, the discussions made in this work are relevant regarding the anti-viral properties of lectins.

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Antiviral Activity of a Turbot (Scophthalmus maximus) NK-Lysin Peptide by Inhibition of Low-pH Virus-Induced Membrane Fusion

Marine Drugs ◽

10.3390/md17020087 ◽

2019 ◽

Vol 17 (2) ◽

pp. 87 ◽

Cited By ~ 11

Author(s):

Alberto Falco ◽

Regla Medina-Gali ◽

José Poveda ◽

Melissa Bello-Perez ◽

Beatriz Novoa ◽

...

Keyword(s):

Antiviral Activity ◽

Viral Infections ◽

Scophthalmus Maximus ◽

Low Ph ◽

Host Cells ◽

Viral Origin ◽

Membrane Rupture ◽

Viral Particles ◽

Strong Antiviral Activity ◽

Turbot Scophthalmus Maximus

Global health is under attack by increasingly-frequent pandemics of viral origin. Antimicrobial peptides are a valuable tool to combat pathogenic microorganisms. Previous studies from our group have shown that the membrane-lytic region of turbot (Scophthalmus maximus) NK-lysine short peptide (Nkl71–100) exerts an anti-protozoal activity, probably due to membrane rupture. In addition, NK-lysine protein is highly expressed in zebrafish in response to viral infections. In this work several biophysical methods, such as vesicle aggregation, leakage and fluorescence anisotropy, are employed to investigate the interaction of Nkl71–100 with different glycerophospholipid vesicles. At acidic pH, Nkl71–100 preferably interacts with phosphatidylserine (PS), disrupts PS membranes, and allows the content leakage from vesicles. Furthermore, Nkl71–100 exerts strong antiviral activity against spring viremia of carp virus (SVCV) by inhibiting not only the binding of viral particles to host cells, but also the fusion of virus and cell membranes, which requires a low pH context. Such antiviral activity seems to be related to the important role that PS plays in these steps of the replication cycle of SVCV, a feature that is shared by other families of virus-comprising members with health and veterinary relevance. Consequently, Nkl71–100 is shown as a promising broad-spectrum antiviral candidate.

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Application of Viral Vectors for Vaccine Development with a Special Emphasis on COVID-19

Viruses ◽

10.3390/v12111324 ◽

2020 ◽

Vol 12 (11) ◽

pp. 1324

Author(s):

Kenneth Lundstrom

Keyword(s):

Neutralizing Antibodies ◽

Viral Vectors ◽

Vaccine Development ◽

Viral Vector ◽

Recombinant Protein Expression ◽

Surface Proteins ◽

Viral Particles ◽

Preclinical Animal Models ◽

Viral Surface ◽

Lethal Doses

Viral vectors can generate high levels of recombinant protein expression providing the basis for modern vaccine development. A large number of different viral vector expression systems have been utilized for targeting viral surface proteins and tumor-associated antigens. Immunization studies in preclinical animal models have evaluated the elicited humoral and cellular responses and the possible protection against challenges with lethal doses of infectious pathogens or tumor cells. Several vaccine candidates for both infectious diseases and various cancers have been subjected to a number of clinical trials. Human immunization trials have confirmed safe application of viral vectors, generation of neutralizing antibodies and protection against challenges with lethal doses. A special emphasis is placed on COVID-19 vaccines based on viral vectors. Likewise, the flexibility and advantages of applying viral particles, RNA replicons and DNA replicon vectors of self-replicating RNA viruses for vaccine development are presented.

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Mathematical Modeling of Autoimmune Diseases

Symmetry ◽

10.3390/sym12091457 ◽

2020 ◽

Vol 12 (9) ◽

pp. 1457

Author(s):

Mikhail Kolev

Keyword(s):

Immune System ◽

Autoimmune Diseases ◽

Viral Infections ◽

Nonequilibrium Statistical Mechanics ◽

Good Health ◽

The Body ◽

Host Cells ◽

Human Organism ◽

Viral Particles ◽

Harmful Effects

The human organism is a very complex system. To be in good health, its components must function properly. One of the most important systems of an organism is the immune system. It protects the body from the harmful effects of various external and internal agents. Sometimes, however, the immune system starts attacking its own healthy cells, tissues and organs. Then autoimmune diseases arise. They are widespread in recent decades. There is evidence that often autoimmune responses occur due to viral infections. In this paper, a new mathematical model of a general autoimmune disease is proposed. It describes the interactions between viral particles and host cells. The model is formulated by using integro-differential equations of Boltzmann type. This approach is typical for the nonequilibrium statistical mechanics. A preliminary qualitative and quantitative analysis of the model is presented.

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Plant-Derived Food Grade Substances (PDFGS) Active Against Respiratory Viruses: A Systematic Review of Non-clinical Studies

Frontiers in Nutrition ◽

10.3389/fnut.2021.606782 ◽

2021 ◽

Vol 8 ◽

Author(s):

Francis U. Umeoguaju ◽

Benson C. Ephraim-Emmanuel ◽

Kingsley C. Patrick-Iwuanyanwu ◽

Judith T. Zelikoff ◽

Orish Ebere Orisakwe

Keyword(s):

Respiratory Tract ◽

Respiratory Viruses ◽

Host Cells ◽

Food Plants ◽

Influenza B Virus ◽

Influenza B ◽

Human Populations ◽

Human Respiratory Tract ◽

Food Grade ◽

Pathogenic Viruses

Human diet comprises several classes of phytochemicals some of which are potentially active against human pathogenic viruses. This study examined available evidence that identifies existing food plants or constituents of edible foods that have been reported to inhibit viral pathogenesis of the human respiratory tract. SCOPUS and PUBMED databases were searched with keywords designed to retrieve articles that investigated the effect of plant-derived food grade substances (PDFGS) on the activities of human pathogenic viruses. Eligible studies for this review were those done on viruses that infect the human respiratory tract. Forty six (46) studies met the specified inclusion criteria from the initial 5,734 hits. The selected studies investigated the effects of different PDFGS on the infectivity, proliferation and cytotoxicity of different respiratory viruses including influenza A virus (IAV), influenza B virus (IBV), Respiratory syncytial virus (RSV), human parainfluenza virus (hPIV), Human coronavirus NL63 (HCoV-NL63), and rhinovirus (RV) in cell lines and mouse models. This review reveals that PDFGS inhibits different stages of the pathological pathways of respiratory viruses including cell entry, replication, viral release and viral-induced dysregulation of cellular homeostasis and functions. These alterations eventually lead to the reduction of virus titer, viral-induced cellular damages and improved survival of host cells. Major food constituents active against respiratory viruses include flavonoids, phenolic acids, tannins, lectins, vitamin D, curcumin, and plant glycosides such as glycyrrhizin, acteoside, geniposide, and iridoid glycosides. Herbal teas such as guava tea, green and black tea, adlay tea, cistanche tea, kuding tea, licorice extracts, and edible bird nest extracts were also effective against respiratory viruses in vitro. The authors of this review recommend an increased consumption of foods rich in these PDFGS including legumes, fruits (e.g berries, citrus), tea, fatty fish and curcumin amongst human populations with high prevalence of respiratory viral infections in order to prevent, manage and/or reduce the severity of respiratory virus infections.

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Aptamers for Anti-Viral Therapeutics and Diagnostics

International Journal of Molecular Sciences ◽

10.3390/ijms22084168 ◽

2021 ◽

Vol 22 (8) ◽

pp. 4168

Author(s):

Tae-Hyeong Kim ◽

Seong-Wook Lee

Keyword(s):

Viral Infections ◽

Modern Medicine ◽

Host Cells ◽

Form Of Life ◽

Appropriate Treatment ◽

Viral Particles ◽

Infected Cells ◽

Viral Diagnosis ◽

Exponential Enrichment ◽

Therapeutic Perspective

Viral infections cause a host of fatal diseases and seriously affect every form of life from bacteria to humans. Although most viral infections can receive appropriate treatment thereby limiting damage to life and livelihood with modern medicine and early diagnosis, new types of viral infections are continuously emerging that need to be properly and timely treated. As time is the most important factor in the progress of many deadly viral diseases, early detection becomes of paramount importance for effective treatment. Aptamers are small oligonucleotide molecules made by the systematic evolution of ligands by exponential enrichment (SELEX). Aptamers are characterized by being able to specifically bind to a target, much like antibodies. However, unlike antibodies, aptamers are easily synthesized, modified, and are able to target a wider range of substances, including proteins and carbohydrates. With these advantages in mind, many studies on aptamer-based viral diagnosis and treatments are currently in progress. The use of aptamers for viral diagnosis requires a system that recognizes the binding of viral molecules to aptamers in samples of blood, serum, plasma, or in virus-infected cells. From a therapeutic perspective, aptamers target viral particles or host cell receptors to prevent the interaction between the virus and host cells or target intracellular viral proteins to interrupt the life cycle of the virus within infected cells. In this paper, we review recent attempts to use aptamers for the diagnosis and treatment of various viral infections.

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A widespread viral entry mechanism: The C-end Rule motif–neuropilin receptor interaction

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2112457118 ◽

2021 ◽

Vol 118 (49) ◽

pp. e2112457118

Author(s):

Giuseppe Balistreri ◽

Yohei Yamauchi ◽

Tambet Teesalu

Keyword(s):

Cell Surface ◽

Viral Entry ◽

Surface Proteins ◽

Receptor Interaction ◽

Growth Factor Signaling ◽

Surface Receptors ◽

Viral Particles ◽

Carboxy Terminal ◽

Viral Surface ◽

Entry Mechanism

Many phylogenetically distant animal viruses, including the new coronavirus severe acute respiratory syndrome coronavirus 2, have surface proteins with polybasic sites that are cleaved by host furin and furin-like proteases. Other than priming certain viral surface proteins for fusion, cleavage generates a carboxy-terminal RXXR sequence. This C-end Rule (CendR) motif is known to bind to neuropilin (NRP) receptors on the cell surface. NRPs are ubiquitously expressed, pleiotropic cell surface receptors with important roles in growth factor signaling, vascular biology, and neurobiology, as well as immune homeostasis and activation. The CendR–NRP receptor interaction promotes endocytic internalization and tissue spreading of different cargo, including viral particles. We propose that the interaction between viral surface proteins and NRPs plays an underappreciated and prevalent role in the transmission and pathogenesis of diverse viruses and represents a promising broad-spectrum antiviral target.

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Structure-Based Vaccine Antigen Design

Annual Review of Medicine ◽

10.1146/annurev-med-121217-094234 ◽

2019 ◽

Vol 70 (1) ◽

pp. 91-104 ◽

Cited By ~ 34

Author(s):

Barney S. Graham ◽

Morgan S.A. Gilman ◽

Jason S. McLellan

Keyword(s):

Vaccine Development ◽

Structural Information ◽

Protein Structures ◽

Surface Protein ◽

Surface Proteins ◽

Vaccine Antigen ◽

Viral Fusion ◽

Emerging Pathogens ◽

Syncytial Virus ◽

Viral Surface

Enabled by new approaches for rapid identification and selection of human monoclonal antibodies, atomic-level structural information for viral surface proteins, and capacity for precision engineering of protein immunogens and self-assembling nanoparticles, a new era of antigen design and display options has evolved. While HIV-1 vaccine development has been a driving force behind these technologies and concepts, clinical proof-of-concept for structure-based vaccine design may first be achieved for respiratory syncytial virus (RSV), where conformation-dependent access to neutralization-sensitive epitopes on the fusion glycoprotein determines the capacity to induce potent neutralizing activity. Success with RSV has motivated structure-based stabilization of other class I viral fusion proteins for use as immunogens and demonstrated the importance of structural information for developing vaccines against other viral pathogens, particularly difficult targets that have resisted prior vaccine development efforts. Solving viral surface protein structures also supports rapid vaccine antigen design and application of platform manufacturing approaches for emerging pathogens.

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Antiviral Strategies Using Natural Source-Derived Sulfated Polysaccharides in the Light of the COVID-19 Pandemic and Major Human Pathogenic Viruses

Viruses ◽

10.3390/v14010035 ◽

2021 ◽

Vol 14 (1) ◽

pp. 35

Author(s):

Bimalendu Ray ◽

Imran Ali ◽

Subrata Jana ◽

Shuvam Mukherjee ◽

Saikat Pal ◽

...

Keyword(s):

Antiviral Activity ◽

Viral Infection ◽

Molecular Mechanisms ◽

Viral Infections ◽

Structural Characteristics ◽

Antiviral Agents ◽

Host Cells ◽

Sulfated Polysaccharides ◽

Susceptible Host ◽

Pathogenic Viruses

Only a mere fraction of the huge variety of human pathogenic viruses can be targeted by the currently available spectrum of antiviral drugs. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak has highlighted the urgent need for molecules that can be deployed quickly to treat novel, developing or re-emerging viral infections. Sulfated polysaccharides are found on the surfaces of both the susceptible host cells and the majority of human viruses, and thus can play an important role during viral infection. Such polysaccharides widely occurring in natural sources, specifically those converted into sulfated varieties, have already proved to possess a high level and sometimes also broad-spectrum antiviral activity. This antiviral potency can be determined through multifold molecular pathways, which in many cases have low profiles of cytotoxicity. Consequently, several new polysaccharide-derived drugs are currently being investigated in clinical settings. We reviewed the present status of research on sulfated polysaccharide-based antiviral agents, their structural characteristics, structure–activity relationships, and the potential of clinical application. Furthermore, the molecular mechanisms of sulfated polysaccharides involved in viral infection or in antiviral activity, respectively, are discussed, together with a focus on the emerging methodology contributing to polysaccharide-based drug development.

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Important Roles of Oligo- and Polysaccharides against SARS-CoV-2: Recent Advances

Applied Sciences ◽

10.3390/app11083512 ◽

2021 ◽

Vol 11 (8) ◽

pp. 3512

Author(s):

Siavash Iravani ◽

Rajender S. Varma

Keyword(s):

Public Health ◽

Antiviral Activity ◽

Immune Regulation ◽

Viral Infections ◽

Vaccine Adjuvants ◽

Future Perspectives ◽

Plant Polysaccharides ◽

The World ◽

Pathogenic Viruses ◽

Low Toxicity

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-initiated outbreak of COVID-19 has spread rapidly around the world, posing a huge threat to public health. Natural oligo- and polysaccharides with low toxicity, good sustainability, high biocompatibility, respectable safety, immune regulation, and antiviral activity can be employed as promising candidates for the prevention and inhibition of viral infections, especially COVID-19. Glycosaminoglycans, marine polysaccharides, terrestrial plant polysaccharides, and some others have exhibited potential antiviral activity against pathogenic viruses, in the format of polysaccharide-centered vaccine adjuvants, nano-based structures, drug conveyance platforms, etc. In this review, significant recent advancements pertaining to the antiviral applications of oligo- and polysaccharides against SARS-CoV-2 are highlighted, including important challenges and future perspectives.

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