Pharmacologic Considerations for Antiviral Drug Development

OBJECTIVE: To discuss pharmacologic considerations for the development of antiviral agents. DATA SOURCES: English-language literature pertaining to the development and clinical evaluation of antiviral compounds, primarily agents targeted against herpes group viruses and HIV. STUDY SELECTION AND DATA EXTRACTION: Pertinent information, as judged by the author, was selected for discussion. DATA SYNTHESIS: Drug development of antiviral agents presents unique problems compared with that of antimicrobial and other agents. Understanding the mechanism of action and both pharmacokinetic and pharmacodynamic considerations is critical to developing a rational dosing strategy and safe, effective use. The lack of standardized methods for antiviral susceptibility testing and the influence of factors such as strain of virus, host cell type, culture medium, inoculum size, end point, and method of measurement on the results obtained illustrate factors that complicate preclinical pharmacologic analysis of antiviral agents. Acyclovir offers a model for clinical drug development. Its mechanism of action, pharmacokinetics, and pharmacodynamics have been studied extensively. Rational guidelines for usage are available, including guidelines in special patient populations such as kidney transplant recipients and neonates. A pregnancy registry has allowed evaluation of the incidence of birth defects in fetuses exposed to systemic acyclovir. Several pitfalls in antiviral drug development are associated with inadequate pharmacologic information. The development of dextran sulfate and fialuridine provides two examples. Integration of pharmacokinetic and pharmacodynamic analyses using modern sampling and analysis techniques may facilitate more rapid development of antiviral agents and more informed dosage regimens to achieve the highest probability of therapeutic success. CONCLUSIONS: Insufficient knowledge of the pharmacokinetic and pharmacodynamic characteristics of an antiviral agent is a barrier to efficient drug development. Application and early integration of pharmacologic information into clinical investigations hold promise as a means to shorten the development process and, more importantly, to arrive at informative dosing regimens that optimize therapeutic success.

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Nitrogen-Based Heterocyclic Compounds: A Promising Class of Antiviral Agents against Chikungunya Virus

Life ◽

10.3390/life11010016 ◽

2020 ◽

Vol 11 (1) ◽

pp. 16

Author(s):

Andreza C. Santana ◽

Ronaldo C. Silva Filho ◽

José C. J. M. D. S. Menezes ◽

Diego Allonso ◽

Vinícius R. Campos

Keyword(s):

Antiviral Activity ◽

Mechanism Of Action ◽

Heterocyclic Compounds ◽

Chikungunya Virus ◽

Antiviral Agents ◽

Antiviral Drug ◽

Important Class ◽

Available Nitrogen ◽

Global Threat ◽

Present Understanding

Arboviruses, in general, are a global threat due to their morbidity and mortality, which results in an important social and economic impact. Chikungunya virus (CHIKV), one of the most relevant arbovirus currently known, is a re-emergent virus that causes a disease named chikungunya fever, characterized by a severe arthralgia (joint pains) that can persist for several months or years in some individuals. Until now, no vaccine or specific antiviral drug is commercially available. Nitrogen heterocyclic scaffolds are found in medications, such as aristeromycin, favipiravir, fluorouracil, 6-azauridine, thioguanine, pyrimethamine, among others. New families of natural and synthetic nitrogen analogous compounds are reported to have significant anti-CHIKV effects. In the present work, we focus on these nitrogen-based heterocyclic compounds as an important class with CHIKV antiviral activity. We summarize the present understanding on this class of compounds against CHIKV and also present their possible mechanism of action.

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Substrate specificity profiling of SARS-CoV-2 main protease enables design of activity-based probes for patient-sample imaging

10.1101/2020.03.07.981928 ◽

2020 ◽

Cited By ~ 18

Author(s):

Wioletta Rut ◽

Katarzyna Groborz ◽

Linlin Zhang ◽

Xinyuanyuan Sun ◽

Mikolaj Zmudzinski ◽

...

Keyword(s):

Unnatural Amino Acids ◽

Drug Targets ◽

Rapid Development ◽

Antiviral Treatment ◽

Antiviral Agents ◽

Antiviral Drug ◽

International Travel ◽

Substrate Preferences ◽

Main Protease ◽

Novel Coronavirus

AbstractIn December 2019, the first cases of infection with a novel coronavirus, SARS-CoV-2, were diagnosed in Wuhan, China. Due to international travel and human-to-human transmission, the virus spread rapidly inside and outside of China. Currently, there is no effective antiviral treatment for coronavirus disease 2019 (COVID-19); therefore, research efforts are focused on the rapid development of vaccines and antiviral drugs. The SARS-CoV-2 main protease constitutes one of the most attractive antiviral drug targets. To address this emerging problem, we have synthesized a combinatorial library of fluorogenic substrates with glutamine in the P1 position. We used it to determine the substrate preferences of the SARS-CoV and SARS-CoV-2 main proteases, using natural and a large panel of unnatural amino acids. On the basis of these findings, we designed and synthesized an inhibitor and two activity-based probes, for one of which we determined the crystal structure of its complex with the SARS-CoV-2 Mpro. Using this approach we visualized SARS-CoV-2 active Mpro within nasopharyngeal epithelial cells of a patient with active COVID-19 infection. The results of our work provide a structural framework for the design of inhibitors as antiviral agents or diagnostic tests.

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Zinc Oxide Nanoparticles as a Potential Agent for Antiviral Drug Delivery Development; A Systematic Literature Review

Current Nanoscience ◽

10.2174/1573413717666210618103632 ◽

2021 ◽

Vol 17 ◽

Author(s):

Mahda sadat Nasrollahzadeh ◽

Razieh Ghodsi ◽

Farzin Hadizadeh ◽

Mahdi Faal Maleki ◽

Mohammad Mashreghi ◽

...

Keyword(s):

Zinc Oxide ◽

Metal Oxide ◽

Viral Infections ◽

Relevant Literature ◽

Antiviral Agents ◽

Antiviral Drug ◽

Antiviral Agent ◽

Human Studies ◽

Inclusion Criteria ◽

Zno Nps

: Viral infection is a worldwide health problem, which has negatively affected global activity in recent years. There is no specific medication for most viral infections, and the treatments are based on symptom management. Nanoparticles (NPs) in recent years have shown promising antibacterial and antiviral properties, among which metal oxide NPs have shown superiority. In the present study, we aimed to systematically review all available literature supporting the efficiency of zinc oxide (ZnO) NPs in the treatment of viral infections. For this purpose, a systematic literature search was performed in scientific literature databases including PubMed, Scopus, Web of Science, Science Direct, Ovid, Embase, and Google Scholar by using “viral infections”, “antiviral effects,” and “ZnO NPs” in addition to all their equivalent terms as keywords. Due to the lack of human studies, no strict inclusion criteria were defined, and all available relevant literature were included. A total of 14 documents that fully met the inclusion criteria were retrieved and used for data synthesis. The results showed that ZnO NPs, due to some specific physiochemical properties, can be a promising approach in developing antiviral agents and nanovaccines, especially against RNA viruses, such as human immunodeficiency virus (HIV) and severe acute respiratory syndrome coronavirus. The most probable antiviral mechanistic pathways of ZnO NPs were blocking the virus entry into the cells and deactivation of the virus through virostatic potential. Based on the findings of the included studies, it is suggested that ZnO NPs and other metal oxide-based NPs may be a potential antiviral agent; however, further human studies are required to confirm such efficiency in clinical practice.

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Host-Directed Antiviral Therapy

Clinical Microbiology Reviews ◽

10.1128/cmr.00168-19 ◽

2020 ◽

Vol 33 (3) ◽

Cited By ~ 6

Author(s):

Naveen Kumar ◽

Shalini Sharma ◽

Ram Kumar ◽

Bhupendra N. Tripathi ◽

Sanjay Barua ◽

...

Keyword(s):

Drug Resistance ◽

Drug Development ◽

Virus Replication ◽

Antiviral Drug ◽

Antiviral Agent ◽

Drug Resistant ◽

Virus Infections ◽

Alternate Host ◽

Cellular Factors ◽

Rapid Generation

SUMMARY Antiviral drugs have traditionally been developed by directly targeting essential viral components. However, this strategy often fails due to the rapid generation of drug-resistant viruses. Recent genome-wide approaches, such as those employing small interfering RNA (siRNA) or clustered regularly interspaced short palindromic repeats (CRISPR) or those using small molecule chemical inhibitors targeting the cellular “kinome,” have been used successfully to identify cellular factors that can support virus replication. Since some of these cellular factors are critical for virus replication, but are dispensable for the host, they can serve as novel targets for antiviral drug development. In addition, potentiation of immune responses, regulation of cytokine storms, and modulation of epigenetic changes upon virus infections are also feasible approaches to control infections. Because it is less likely that viruses will mutate to replace missing cellular functions, the chance of generating drug-resistant mutants with host-targeted inhibitor approaches is minimized. However, drug resistance against some host-directed agents can, in fact, occur under certain circumstances, such as long-term selection pressure of a host-directed antiviral agent that can allow the virus the opportunity to adapt to use an alternate host factor or to alter its affinity toward the target that confers resistance. This review describes novel approaches for antiviral drug development with a focus on host-directed therapies and the potential mechanisms that may account for the acquisition of antiviral drug resistance against host-directed agents.

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Benzothiazole moieties and their derivatives as antimicrobial and antiviral agents: A mini-review

International Journal of Research in Pharmaceutical Sciences ◽

10.26452/ijrps.v11i3.2459 ◽

2020 ◽

Vol 11 (3) ◽

pp. 3309-3315

Author(s):

Manahil B Elamin ◽

Amani Abd Elrazig Salman Abd Elaziz ◽

Emad Mohamed Abdallah

Keyword(s):

Scientific Literature ◽

Antiviral Agents ◽

Antiviral Drug ◽

Pharmaceutical Chemistry ◽

Heterocyclic Chemistry ◽

Antimicrobial Drugs ◽

Benzothiazole Derivatives ◽

Global Concern ◽

Pharmaceutical Molecules ◽

Heterocyclic Moiety

Heterocyclic chemistry has provided an inexhaustible source of pharmaceutical molecules. Heterocyclic compounds such as benzothiazole moieties and its derivatives area substantial class of compounds in pharmaceutical chemistry and exhibited therapeutic capabilities, such as antitumor, anticancer, antioxidant, antidiabetic, antiviral, antimicrobial, antimalarial, anthelmintic and other activities. Besides, some antibiotics such as penicillin and cephalosporin have heterocyclic moiety. The growing prevalence of multi-drug resistant pathogens represents serious global concern,which requires the development of new antimicrobial drugs. Moreover, the emergence of pandemic SARSCoV-2 causing Covid-19 disease and all these health dilemmas urge the scientific community to examine the possible antimicrobial and antiviral capacities of some bioactive benzothiazole derivatives against these severe causative agents.This mini-review highlights some recent scientific literature on different benzothiazole molecules and their derivatives. It turns out that, there are numerous synthesized benzothiazole derivatives which exhibited different mode of actions against microorganisms or viruses and accordingly suggested them as an active candidate in the discovery of new antimicrobial or antiviral agents for clinical development. The recommended bioactive benzothiazole derivatives mentioned in the current study are mainly Schiff bases, azo dyes and metal complexes benzothiazole derivatives; the starting material for most of these derivatives are 2-aminobenzothiazole although careful pharmaceutical studies should be conducted to ensure the safety and efficacy of these bioactive synthesized molecules as an antimicrobial or antiviral drug in the future.

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Protease Inhibitors as Antiviral Agents

Clinical Microbiology Reviews ◽

10.1128/cmr.11.4.614 ◽

1998 ◽

Vol 11 (4) ◽

pp. 614-627 ◽

Cited By ~ 118

Author(s):

A. K. Patick ◽

K. E. Potts

Keyword(s):

Protease Inhibitors ◽

Viral Infections ◽

Critical Role ◽

Antiviral Agents ◽

Antiviral Agent ◽

Structural Proteins ◽

Viral Protease ◽

Virus Particles ◽

Viral Proteases ◽

Viral Polyprotein

SUMMARY Currently, there are a number of approved antiviral agents for use in the treatment of viral infections. However, many instances exist in which the use of a second antiviral agent would be beneficial because it would allow the option of either an alternative or a combination therapeutic approach. Accordingly, virus-encoded proteases have emerged as new targets for antiviral intervention. Molecular studies have indicated that viral proteases play a critical role in the life cycle of many viruses by effecting the cleavage of high-molecular-weight viral polyprotein precursors to yield functional products or by catalyzing the processing of the structural proteins necessary for assembly and morphogenesis of virus particles. This review summarizes some of the important general features of virus-encoded proteases and highlights new advances and/or specific challenges that are associated with the research and development of viral protease inhibitors. Specifically, the viral proteases encoded by the herpesvirus, retrovirus, hepatitis C virus, and human rhinovirus families are discussed.

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A possible interaction between favipiravir and methotrexate: Drug-induced hepatotoxicity in a patient with osteosarcoma

Journal of Oncology Pharmacy Practice ◽

10.1177/10781552211031304 ◽

2021 ◽

pp. 107815522110313

Author(s):

Emre Demir ◽

Osman Sütcüoğlu ◽

Beril Demir ◽

Oktay Ünsal ◽

Ozan Yazıcı

Keyword(s):

Drug Interactions ◽

Toxic Hepatitis ◽

Antiviral Agents ◽

Antiviral Agent ◽

Aldehyde Oxidase ◽

Chemotherapeutic Agents ◽

High Dose ◽

Drug Induced ◽

Metastatic Osteosarcoma ◽

Grade 3

Introduction Favipiravir is an antiviral agent that is recently used for SARS-CoV2 infection. The drug-drug interactions of favipiravir especially with chemotherapeutic agents in a patient with malignancy are not well known. Case report The patient diagnosed with metastatic osteosarcoma was given high dose methotrexate treatment, and favipiravir was started on the third day of the treatment with suspicion of SARS-CoV2 infection. Grade 3 hepatotoxicity developed after favipiravir. Management & outcome: The acute viral hepatitis panel and autoimmune liver disease panel were negative. The ultrasound of the abdomen was unremarkable for any hepatobiliary pathology. The all viral and hepatobiliary possible etiological factors were ruled out. The patient’s liver enzymes increased just after (12 hours later) the initiation of favipiravir, and we diagnosed toxic hepatitis caused by favipiravir-methotrexate interaction. Therefore, methylprednisolone 1 mg/kg dose was started for a presumed diagnosis of toxic hepatitis. Hepatotoxicity completely regressed after favipiravir was discontinued. Discussion Favipiravir may inhibit methotrexate elimination by inhibiting aldehyde oxidase and its sequential use may cause hepatotoxicity in this case. The clinicians should keep in mind possible drug interactions while using new antiviral agents against SARS-CoV2 like favipiravir.

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Heparin Inhibits Cellular Invasion by SARS-CoV-2: Structural Dependence of the Interaction of the Spike S1 Receptor-Binding Domain with Heparin

Thrombosis and Haemostasis ◽

10.1055/s-0040-1721319 ◽

2020 ◽

Vol 120 (12) ◽

pp. 1700-1715

Author(s):

Courtney J. Mycroft-West ◽

Dunhao Su ◽

Isabel Pagani ◽

Timothy R. Rudd ◽

Stefano Elli ◽

...

Keyword(s):

Receptor Binding ◽

Structural Changes ◽

Rapid Development ◽

Antiviral Agents ◽

Vero Cells ◽

Binding Domain ◽

Microbial Pathogens ◽

Minimum Size ◽

Structural Basis ◽

Receptor Binding Domain

AbstractThe dependence of development and homeostasis in animals on the interaction of hundreds of extracellular regulatory proteins with the peri- and extracellular glycosaminoglycan heparan sulfate (HS) is exploited by many microbial pathogens as a means of adherence and invasion. Heparin, a widely used anticoagulant drug, is structurally similar to HS and is a common experimental proxy. Exogenous heparin prevents infection by a range of viruses, including S-associated coronavirus isolate HSR1. Here, we show that heparin inhibits severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) invasion of Vero cells by up to 80% at doses achievable through prophylaxis and, particularly relevant, within the range deliverable by nebulisation. Surface plasmon resonance and circular dichroism spectroscopy demonstrate that heparin and enoxaparin, a low-molecular-weight heparin which is a clinical anticoagulant, bind and induce a conformational change in the spike (S1) protein receptor-binding domain (S1 RBD) of SARS-CoV-2. A library of heparin derivatives and size-defined fragments were used to probe the structural basis of this interaction. Binding to the RBD is more strongly dependent on the presence of 2-O or 6-O sulfate groups than on N-sulfation and a hexasaccharide is the minimum size required for secondary structural changes to be induced in the RBD. It is likely that inhibition of viral infection arises from an overlap between the binding sites of heparin/HS on S1 RBD and that of the angiotensin-converting enzyme 2. The results suggest a route for the rapid development of a first-line therapeutic by repurposing heparin and its derivatives as antiviral agents against SARS-CoV-2 and other members of the Coronaviridae.

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Amantadine Inhibits SARS-CoV-2 In Vitro

Viruses ◽

10.3390/v13040539 ◽

2021 ◽

Vol 13 (4) ◽

pp. 539

Author(s):

Klaus Fink ◽

Andreas Nitsche ◽

Markus Neumann ◽

Marica Grossegesse ◽

Karl-Heinz Eisele ◽

...

Keyword(s):

Influenza A ◽

Antiviral Agents ◽

Antiviral Drug ◽

Systemic Exposure ◽

Topical Administration ◽

Counter Measures ◽

Travel Restrictions ◽

Drug Treatments ◽

Intranasal Instillation

Since the SARS-CoV-2 pandemic started in late 2019, the search for protective vaccines and for drug treatments has become mandatory to fight the global health emergency. Travel restrictions, social distancing, and face masks are suitable counter measures, but may not bring the pandemic under control because people will inadvertently or at a certain degree of restriction severity or duration become incompliant with the regulations. Even if vaccines are approved, the need for antiviral agents against SARS-CoV-2 will persist. However, unequivocal evidence for efficacy against SARS-CoV-2 has not been demonstrated for any of the repurposed antiviral drugs so far. Amantadine was approved as an antiviral drug against influenza A, and antiviral activity against SARS-CoV-2 has been reasoned by analogy but without data. We tested the efficacy of amantadine in vitro in Vero E6 cells infected with SARS-CoV-2. Indeed, amantadine inhibited SARS-CoV-2 replication in two separate experiments with IC50 concentrations between 83 and 119 µM. Although these IC50 concentrations are above therapeutic amantadine levels after systemic administration, topical administration by inhalation or intranasal instillation may result in sufficient amantadine concentration in the airway epithelium without high systemic exposure. However, further studies in other models are needed to prove this hypothesis.

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Chikungunya and Zika Viruses: Co-Circulation and the Interplay between Viral Proteins and Host Factors

Pathogens ◽

10.3390/pathogens10040448 ◽

2021 ◽

Vol 10 (4) ◽

pp. 448

Author(s):

Sineewanlaya Wichit ◽

Nuttamonpat Gumpangseth ◽

Rodolphe Hamel ◽

Sakda Yainoy ◽

Siwaret Arikit ◽

...

Keyword(s):

Antiviral Drug ◽

Virus Transmission ◽

Antiviral Agent ◽

Viral Proteins ◽

Targeted Therapeutics ◽

Limited Information ◽

Mosquito Vectors ◽

Host Proteins ◽

Host Interactions ◽

Viral Host Interactions

Chikungunya and Zika viruses, both transmitted by mosquito vectors, have globally re-emerged over for the last 60 years and resulted in crucial social and economic concerns. Presently, there is no specific antiviral agent or vaccine against these debilitating viruses. Understanding viral–host interactions is needed to develop targeted therapeutics. However, there is presently limited information in this area. In this review, we start with the updated virology and replication cycle of each virus. Transmission by similar mosquito vectors, frequent co-circulation, and occurrence of co-infection are summarized. Finally, the targeted host proteins/factors used by the viruses are discussed. There is an urgent need to better understand the virus–host interactions that will facilitate antiviral drug development and thus reduce the global burden of infections caused by arboviruses.

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