Achievements and Challenges in Antiviral Drug Discovery

2005 ◽  
Vol 16 (3) ◽  
pp. 155-168 ◽  
Author(s):  
Eddy Littler ◽  
Bo Oberg
Keyword(s):  
Antiviral Drug ◽  
Emerging Viruses ◽  
Potential Threat ◽  
Varicella Zoster ◽  
Antiviral Therapies ◽  
Therapeutic Value ◽  
B Virus ◽  
Life Threatening ◽  
Current Therapies ◽  
Simplex Virus

The last 40 years have seen the development of several antiviral drugs with therapeutic value in treating life-threatening or debilitating diseases such as those caused by HIV, hepatitis B virus, herpesviruses (such as herpes simplex virus and varicella zoster virus) and influenza virus. These relatively recent advances have been due to technical breakthroughs in the cultivation of viruses in the laboratory, identification of viral enzymes and, more recently, their molecular biology. We describe here the antecedence of several of the existing antivirals and their strengths and weaknesses. We indicate where the major challenges lie for future improvements of current therapies and possible new indications, such as hepatitis C virus and papillomavirus. We also describe how current antiviral therapies are restricted to a rather limited number of viral diseases of sufficient interest to the pharmaceutical industry. Finally we describe the potential threat of emerging viruses and bio-weapons and the challenges that they present to therapy.

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.

scholarly journals Addressing the selectivity and toxicity of antiviral nucleosides

2018 ◽  
Vol 26 ◽  
pp. 204020661875852 ◽  
Author(s):  
Joy Y Feng
Keyword(s):  
New Drugs ◽  
Attrition Rate ◽  
Emerging Viruses ◽  
Herpes Simplex Virus 1 ◽  
Nucleotide Analogs ◽  
Antiviral Therapies ◽  
Animal Toxicity ◽  
Simplex Virus ◽  
Antiviral Nucleosides ◽  
High Attrition Rate

Nucleoside and nucleotide analogs have played significant roles in antiviral therapies and are valued for their impressive potency and high barrier to resistance. They have been approved for treatment of herpes simplex virus-1, HIV, HBV, HCV, and influenza, and new drugs are being developed for the treatment of RSV, Ebola, coronavirus MERS, and other emerging viruses. However, this class of compounds has also experienced a high attrition rate in clinical trials due to toxicity. In this review, we discuss the utility of different biochemical and cell-based assays and provide recommendations for assessing toxicity liability before entering animal toxicity studies.

scholarly journals Rituximab-Based Treatment, HCV Replication, and Hepatic Flares

2012 ◽  
Vol 2012 ◽  
pp. 1-5 ◽  
Author(s):  
Evangelista Sagnelli ◽  
Mariantonietta Pisaturo ◽  
Caterina Sagnelli ◽  
Nicola Coppola
Keyword(s):  
B Cell ◽  
Parvovirus B19 ◽  
Human Monoclonal Antibody ◽  
Chimeric Mouse ◽  
Varicella Zoster ◽  
Hepatic Cells ◽  
B Virus ◽  
Life Threatening ◽  
A Cell ◽  
Hepatic Flare

Rituximab, a chimeric mouse-human monoclonal antibody directed to the CD20 antigen expressed on pre-B lymphocytes and mature lymphocytes, causes a profound B-cell depletion. Due to its peculiar characteristics, this drug has been used to treat oncohaematological diseases, B cell-related autoimmune diseases, rheumatoid arthritis, and, more recently, HCV-associated mixed cryoglobulinaemic vasculitis. Rituximab-based treatment, however, may induce an increased replication of several viruses such as hepatitis B virus, cytomegalovirus, varicella-zoster virus, echovirus, and parvovirus B19. Recent data suggest that rituximab-based chemotherapy induces an increase in HCV expression in hepatic cells, which may become a target for a cell-mediated immune reaction after the withdrawal of treatment and the restoration of the immune control. Only afewsmall studies have investigated the occurrence of HCV reactivation and an associated hepatic flare in patients with oncohaematological diseases receiving R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). These studies suggest that the hepatic flares are frequently asymptomatic, but life-threatening liver failure occurs in nearly 10% of cases.

Treatment of Herpesvirus Infections in Hiv-Infected Individuals

1992 ◽  
Vol 26 (7-8) ◽  
pp. 955-962 ◽  
Author(s):  
Courtney V. Fletcher
Keyword(s):  
Data Extraction ◽  
Infected Individual ◽  
Cell Mediated Immunity ◽  
Varicella Zoster ◽  
Drug Of Choice ◽  
Study Selection ◽  
Life Threatening ◽  
Prevention Of Infections ◽  
Herpes Group ◽  
Simplex Virus

OBJECTIVE: To discuss strategies available for the treatment of herpesvirus infections in individuals infected with HIV. DATA SOURCES: Information was obtained from controlled and uncontrolled clinical trials, abstracts, conference proceedings, and review articles. STUDY SELECTION: Emphasis was placed on controlled investigations in subjects infected with HIV. DATA EXTRACTION: Data from human studies were extracted by the author and evaluated according to the patient population studied, sample size, dosage regimen, and therapeutic response. DATA SYNTHESIS: Herpes group viruses are common opportunistic pathogens in HIV-infected individuals. Zoster, caused by varicella-zoster virus (VZV), is an early indication of the loss of cell-mediated immunity and HIV disease progression. Anorectal mucocutaneous disease is the most common manifestation caused by herpes simplex virus (HSV). Acyclovir is the drug of choice for treatment of both VZV and HSV infections. Cytomegalovirus (CMV) is the most common life-threatening viral infection in patients with AIDS; retinitis is the most frequent clinical manifestation. The response rate of CMV retinitis to initial treatment with either ganciclovir or foscarnet is equivalent, approximately 60–90 percent. Recent data suggest that the survival benefit may be greater with foscarnet. CONCLUSIONS: Advances in the development and application of antiviral drugs for herpes group viruses have made treatment and, in some cases, prevention of infections possible. Future efforts, aimed at earlier intervention and suppression of latent virus, may offer additional improvement in quality of life for the HIV-infected individual.

scholarly journals Antiviral Therapy for Varicella Zoster Virus (VZV) and Herpes Simplex Virus (HSV)-Induced Anterior Uveitis: A Systematic Review and Meta-Analysis

2021 ◽  
Vol 8 ◽  
Author(s):  
Ilaria Testi ◽  
Kanika Aggarwal ◽  
Nishant Jaiswal ◽  
Neha Dahiya ◽  
Zheng Xian Thng ◽  
...  
Keyword(s):  
Systematic Review ◽  
Herpes Simplex ◽  
Anterior Uveitis ◽  
Meta Analysis ◽  
Oral Acyclovir ◽  
Varicella Zoster ◽  
Antiviral Therapies ◽  
Simplex Virus ◽  
Topical Acyclovir ◽  
Significant Superiority

Topic: Herpes simplex virus (HSV) and varicella zoster virus (VZV) are the most common ocular pathogens associated with infectious anterior uveitis. Currently, there are a number of antiviral agents administered to treat viral anterior uveitis (VAU). However, there is no consensus or guidelines about the most appropriate approach leading for the best treatment outcomes with fewer ocular complications.Clinical Relevance: To perform a systematic review and meta-analysis of the efficacy of different antiviral therapies in the management of anterior uveitis secondary to HSV and VZV.Methods: We searched PubMed, Web of Science, CINAHL, OVID, and Embase up to January 2020. Randomized trials, non-randomized intervention studies, controlled before and after studies and observational studies assessing the effect of oral and or topical treatments for VAU were considered. Data extraction and analysis with evaluation of the risk of bias in the included trials were performed.Results: Oral acyclovir demonstrated a statistically significant good treatment outcome in the management of VZV anterior uveitis (vs. placebo) (OR 0.26, 95% CI 0.11–0.59), but did not have similar effect in HSV anterior uveitis (OR 0.47, 95% CI 0.15–1.50). In the treatment of VZV anterior uveitis, there was significant superiority of oral acyclovir−7 day course—over topical acyclovir (OR 4.17, 95% CI 1.28–13.52). Whereas, there was no significant superiority of one of the following treatment regimens over the others: topical acyclovir over topical corticosteroids (OR 1.86, 95% CI 0.67–5.17), and oral acyclovir−7 day course—over oral acyclovir−14 day course—(OR 0.21, 95% CI 0.01–4.50) or oral valaciclovir (OR 1.40, 95% CI 0.48–4.07).Conclusion: Treatment of HSV and VZV anterior uveitis is currently based on individual experiences and limited literature, largely due to weak clinical trial evidence in this regard. Our results highlight the existence of a substantial gap in our evidence base. This finding might contribute to future research studies to ascertain the role of different antiviral therapies in the treatment of VAU.Systematic Review Registration: PROSPERO registration number: CRD420202 00404.

Assembly of VP26 in herpes simplex virus-1 capsid implicated by 3-D structure of recombinant capsid

1995 ◽  
Vol 53 ◽  
pp. 840-841
Author(s):  
Z. Hong Zhou ◽  
Jing He ◽  
Joanita Jakana ◽  
J. D. Tatman ◽  
Frazer J. Rixon ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
3D Structure ◽  
Structure Study ◽  
Herpes Simplex Virus 1 ◽  
Shell Proteins ◽  
Life Threatening ◽  
Infected Cells ◽  
Simplex Virus ◽  
Hsv 1

Herpes simplex virus-1 (HSV-1) is a ubiquitous virus which is implicated in diseases ranging from self-curing cold sores to life-threatening infections. The 2500 Å diameter herpes virion is composed of a glycoprotein spike containing, lipid envelope, enclosing a protein layer (the tegument) in which is embedded the capsid (which contains the dsDNA genome). The B-, and A- and C-capsids, representing different morphogenetic stages in HSV-1 infected cells, are composed of 7, and 5 structural proteins respectively. The three capsid types are organized in similar T=16 icosahedral shells with 12 pentons, 150 hexons, and 320 connecting triplexes. Our previous 3D structure study at 26 Å revealed domain features of all these structural components and suggested probable locations for the outer shell proteins, VP5, VP26, VP19c and VP23. VP5 makes up most of both pentons and hexons. VP26 appeared to bind to the VP5 subunit in hexon but not to that in penton.

scholarly journals Varicella-Zoster Virus and Herpes Simplex Virus 1 Differentially Modulate NKG2D Ligand Expression during Productive Infection

2015 ◽  
Vol 89 (15) ◽  
pp. 7932-7943 ◽  
Author(s):  
Tessa M. Campbell ◽  
Brian P. McSharry ◽  
Megan Steain ◽  
Barry Slobedman ◽  
Allison Abendroth
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Cell Activity ◽  
Nkg2d Ligand ◽  
Nk Cell Activity ◽  
Herpes Simplex Virus 1 ◽  
Varicella Zoster ◽  
Ligand Expression ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACTNatural killer (NK) cell-deficient patients are particularly susceptible to severe infection with herpesviruses, especially varicella-zoster virus (VZV) and herpes simplex virus 1 (HSV-1). The critical role that NK cells play in controlling these infections denotes an intricate struggle for dominance between virus and NK cell antiviral immunity; however, research in this area has remained surprisingly limited. Our study addressed this absence of knowledge and found that infection with VZV was not associated with enhanced NK cell activation, suggesting that the virus uses specific mechanisms to limit NK cell activity. Analysis of viral regulation of ligands for NKG2D, a potent activating receptor ubiquitously expressed on NK cells, revealed that VZV differentially modulates expression of the NKG2D ligands MICA, ULBP2, and ULBP3 by upregulating MICA expression while reducing ULBP2 and ULBP3 expression on the surface of infected cells. Despite being closely related to VZV, infection with HSV-1 produced a remarkably different effect on NKG2D ligand expression. A significant decrease in MICA, ULBP2, and ULBP3 was observed with HSV-1 infection at a total cellular protein level, as well as on the cell surface. We also demonstrate that HSV-1 differentially regulates expression of an additional NKG2D ligand, ULBP1, by reducing cell surface expression while total protein levels are unchanged. Our findings illustrate both a striking point of difference between two closely related alphaherpesviruses, as well as suggest a powerful capacity for VZV and HSV-1 to evade antiviral NK cell activity through novel modulation of NKG2D ligand expression.IMPORTANCEPatients with deficiencies in NK cell function experience an extreme susceptibility to infection with herpesviruses, in particular, VZV and HSV-1. Despite this striking correlation, research into understanding how these two alphaherpesviruses interact with NK cells is surprisingly limited. Through examination of viral regulation of ligands to the activating NK cell receptor NKG2D, we reveal patterns of modulation by VZV, which were unexpectedly varied in response to regulation by HSV-1 infection. Our study begins to unravel the undoubtedly complex interactions that occur between NK cells and alphaherpesvirus infection by providing novel insights into how VZV and HSV-1 manipulate NKG2D ligand expression to modulate NK cell activity, while also illuminating a distinct variation between two closely related alphaherpesviruses.

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.

scholarly journals Discovery of a Small Molecule Inhibitor of Human Adenovirus Capable of Preventing Escape from the Endosome

2021 ◽  
Vol 22 (4) ◽  
pp. 1617
Author(s):  
Jimin Xu ◽  
Judith Berastegui-Cabrera ◽  
Marta Carretero-Ledesma ◽  
Haiying Chen ◽  
Yu Xue ◽  
...  
Keyword(s):  
Potent Inhibitor ◽  
Antiviral Drug ◽  
Human Adenovirus ◽  
Yield Reduction ◽  
Respiratory Illnesses ◽  
Molecule Inhibitor ◽  
Wide Range ◽  
Ic50 Values ◽  
Life Threatening ◽  
Salicylamide Derivatives

Human adenoviruses (HAdVs) display a wide range of tissue tropism and can cause an array of symptoms from mild respiratory illnesses to disseminated and life-threatening infections in immunocompromised individuals. However, no antiviral drug has been approved specifically for the treatment of HAdV infections. Herein, we report our continued efforts to optimize salicylamide derivatives and discover compound 16 (JMX0493) as a potent inhibitor of HAdV infection. Compound 16 displays submicromolar IC50 values, a higher selectivity index (SI > 100) and 2.5-fold virus yield reduction compared to our hit compound niclosamide. Moreover, unlike niclosamide, our mechanistic studies suggest that the antiviral activity of compound 16 against HAdV is achieved through the inhibition of viral particle escape from the endosome, which bars subsequent uncoating and the presentation of lytic protein VI.

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