Potential Antiviral Action of Alkaloids

Viral infections and outbreaks have become a major concern and are one of the main causes of morbidity and mortality worldwide. The development of successful antiviral therapeutics and vaccines remains a daunting challenge. The discovery of novel antiviral agents is a public health emergency, and extraordinary efforts are underway globally to identify safe and effective treatments for different viral diseases. Alkaloids are natural phytochemicals known for their biological activities, many of which have been intensively studied for their broad-spectrum of antiviral activities against different DNA and RNA viruses. The purpose of this review was to summarize the evidence supporting the efficacy of the antiviral activity of plant alkaloids at half-maximum effective concentration (EC₅₀) or half-maximum inhibitory concentration (IC₅₀) below 10 μM and describe the molecular sites most often targeted by natural alkaloids acting against different virus families. This review highlights that considering the devastating effects of virus pandemics on humans, plants, and animals, the development of high efficiency and low-toxicity antiviral drugs targeting these viruses need to be developed. Furthermore, it summarizes the current research status of alkaloids as the source of antiviral drug development, their structural characteristics, and antiviral targets. Overall, the influence of alkaloids at the molecular level suggests a high degree of specificity which means they could serve as potent and safe antiviral agents waiting for evaluation and exploitation.     

Synthesis and Applications of Nitrogen-Containing Heterocycles as Antiviral Agents

Viruses have been a long-term source of infectious diseases that can lead to large-scale infections and massive deaths. Especially with the recent highly contagious coronavirus (COVID-19), antiviral drugs were developed nonstop to deal with the emergence of new viruses and subject to drug resistance. Nitrogen-containing heterocycles have compatible structures and properties with exceptional biological activity for the drug design of antiviral agents. They provided a broad spectrum of interference against viral infection at various stages, from blocking early viral entry to disrupting the viral genome replication process by targeting different enzymes and proteins of viruses. This review focused on the synthesis and application of antiviral agents derived from various nitrogen-containing heterocycles, such as indole, pyrrole, pyrimidine, pyrazole, and quinoline, within the last ten years. The synthesized scaffolds target HIV, HCV/HBV, VZV/HSV, SARS-CoV, COVID-19, and influenza viruses.     

Synthesis and Antiviral Activity of Camphene Derivatives against Different Types of Viruses

To date, the ‘one bug-one drug’ approach to antiviral drug development cannot effectively respond to the constant threat posed by an increasing diversity of viruses causing outbreaks of viral infections that turn out to be pathogenic for humans. Evidently, there is an urgent need for new strategies to develop efficient antiviral agents with broad-spectrum activities. In this paper, we identified camphene derivatives that showed broad antiviral activities in vitro against a panel of enveloped pathogenic viruses, including influenza virus A/PR/8/34 (H1N1), Ebola virus (EBOV), and the Hantaan virus. The lead-compound 2a, with pyrrolidine cycle in its structure, displayed antiviral activity against influenza virus (IC₅₀ = 45.3 µM), Ebola pseudotype viruses (IC₅₀ = 0.12 µM), and authentic EBOV (IC₅₀ = 18.3 µM), as well as against pseudoviruses with Hantaan virus Gn-Gc glycoprotein (IC₅₀ = 9.1 µM). The results of antiviral activity studies using pseudotype viruses and molecular modeling suggest that surface proteins of the viruses required for the fusion process between viral and cellular membranes are the likely target of compound 2a. The key structural fragments responsible for efficient binding are the bicyclic natural framework and the nitrogen atom. These data encourage us to conduct further investigations using bicyclic monoterpenoids as a scaffold for the rational design of membrane-fusion targeting inhibitors.     

Simultaneous measurements of X-ray diffraction–differential scanning calorimetry

Journal of Thermal Analysis and Calorimetry - Ganciclovir (GCV) is an antiviral drug for treating cytomegalovirus infections. This drug is reported to exist in four crystal forms in the solid...     

Design,Synthesis, and Evaluation of Bioactive Small Molecules

Collaborative research projects between chemists, biologists, and medical scientists have inevitably produced many useful drugs, biosensors, and medical instrumentation. Organic chemistry lies at the heart of drug discovery and development. The current range of organic synthetic methodologies allows for the construction of unlimited libraries of small organic molecules for drug screening. In translational research projects, we have focused on the discovery of lead compounds for three major diseases: Alzheimer's disease (AD), breast cancer, and viral infections. In the AD project, we have taken a rational‐design approach and synthesized a new class of tricyclic pyrone (TP) compounds that preserve memory and motor functions in amyloid precursor protein (APP)/presenilin‐1 (PS1) mice. TPs could protect neuronal death through several possible mechanisms, including their ability to inhibit the formation of both intraneuronal and extracellular amyloid β (Aβ) aggregates, to increase cholesterol efflux, to restore axonal trafficking, and to enhance long‐term potentiation (LTP) and restored LTP following treatment with Aβ oligomers. We have also synthesized a new class of gap‐junction enhancers, based on substituted quinolines, that possess potent inhibitory activities against breast‐cancer cells in vitro and in vivo. Although various antiviral drugs are available, the emergence of viral resistance to existing antiviral drugs and various understudied viral infections, such as norovirus and rotavirus, emphasizes the demand for the development of new antiviral agents against such infections and others. Our laboratories have undertaken these projects for the discovery of new antiviral inhibitors. The discussion of these aforementioned projects may shed light on the future development of drug candidates in the fields of AD, cancer, and viral infections.     

Anti-SARS-CoV-2 Inhibitory Profile of New Quinoline Compounds in Cell Culture-Based Infection Models

The presently ongoing pandemic of human SARS-CoV-2 infections (COVID-19) presents an enormous challenge in surveillance, vaccine and antiviral drug development. Here we report the synthesis of new bioactive quinoline-morpholine hybrid compounds and their virological evaluation, which proves pronounced cell culture-based inhibitory profile against SARS-CoV-2. Thus, selected quinoline compounds may suggest specific hit-to-lead development.     

Natural Products and Their Derivatives against Human Herpesvirus Infection

Herpesviruses establish long-term latent infection for the life of the host and are known to cause numerous diseases. The prevalence of viral infection is significantly increased and causes a worldwide challenge in terms of health issues due to drug resistance. Prolonged treatment with conventional antiviral drugs is more likely to develop drug-resistant strains due to mutations of thymidine nucleoside kinase or DNA polymerase. Hence, the development of alternative treatments is clearly required. Natural products and their derivatives have played a significant role in treating herpesvirus infection rather than nucleoside analogs in drug-resistant strains with minimal undesirable effects and different mechanisms of action. Numerous plants, animals, fungi, and bacteria-derived compounds have been proved to be efficient and safe for treating human herpesvirus infection. This review covers the natural antiherpetic agents with the chemical structural class of alkaloids, flavonoids, terpenoids, polyphenols, anthraquinones, anthracyclines, and miscellaneous compounds, and their antiviral mechanisms have been summarized. This review would be helpful to get a better grasp of anti-herpesvirus activity of natural products and their derivatives, and to evaluate the feasibility of natural compounds as an alternative therapy against herpesvirus infections in humans.     

A review on synthesis of antiviral drugs,in silico studies and their toxicity

Viruses have been around us for a long period of time; they are reported to affect humans, animals and plant at cellular level by using host's body to dwell and reproduce. The spread of HIV was reported in 1981 and created a global threat to public health. In the areas of basic virology, immunology and pathogenesis of HIV/AIDS, the development of antiretroviral medicines and significant progress has been made in recent years. Majority of these antiviral compounds have the potential to be used as HIV drugs, however they are frequently accompanied with some side effects. With the emergence of the COVID-19, human race is facing a new public health crisis and repurposing of antiviral drugs are being considered to block the function of Mpro of the new corona virus (SARS-CoV-2). This review covers the information related to the synthesis of various types of antiviral drugs and their toxicity. Some of these are used as repurposing drugs to cure patients suffering from other diseases/ infections. Therefore, information for in Silico studies of these antiviral drugs is incorporated. In brief, this review is focused on synthesis of different types of antiviral drugs, their repurposing role as well as toxicity.     

Electrochemical Behavior of an Anti-Viral Drug Valacyclovir at Carbon Paste Electrode and Its Analytical Application

Valacyclovir (VCH) is an antiviral drug, used in the management of viral infections such as herpes simplex and varicella-zoster in humans. It is rapidly converted to acyclovir which has antiviral activity against herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) and Varicella-zoster virus (VZV) both in vitro and in vivo. Electrochemical behavior was studied using cyclic voltammetric method, and the analytical application was studied using differential pulse voltammetric technique. The process on the surface of electrode was found to be irreversible and diffusion controlled. The charge transfer coefficient, heterogeneous rate constant, the number of electron transferred and activation parameters were calculated. Possible free radical reaction mechanism taking place on the surface of electrode was proposed. Calibration plot constructed using differential pulse voltammetric technique and applied for quantitative analysis in pharmaceutical and human urine sample. Limit of detection (LOD) and limit of quantification (LOQ) were calculated and found to be 0.028 and 0.09 μM, respectively. The present work describes the electrochemical behavior of an antiviral drug, VCH and its determination in pharmaceutical samples. The method shows the development of a sensor for selective and sensitive determination of VCH.     

New application of human tumor clonogenic assay to in vitro evaluation of tumor-targeting efficiency of immunoconjugates.

This report proposes an efficient in vitro method for the evaluation of drug targeting with monoclonal antibody as a carrier to tumor cells. Monoclonal antibody (35G; IgG2a) selectively binding to alpha-fetoprotein (AFP) from human hepatoma cells (HuH-7) was conjugated with an anticancer drug, vindesine (VDS). Human tumor clonogenic assay (HTCA) with some modifications was applied to estimate the targeting efficiency of a conjugate (VDS-35G) for the first time. In this assay, VDS-35G was cytotoxically active against HuH-7 cells at a lower concentration (0.5 ng/ml) and for a shorter contact time than VDS (50 ng/ml), while 35G and VDS-normal mouse immunoglobulin conjugate (VDS-n-IgG) were not active against the cells. Both VDS-35G and VDS-n-IgG were inactive against HuH-13 cells established from a human hepatocellular carcinoma producing no AFP. In the conventional monolayer culture assay (MCA), VDS-35G showed little effect on HuH-7 cells at the concentration effective in HTCA. The cytotoxic activity of VDS in MCA was similar to that in HTCA but the cytotoxic activity of VDS-35G in MCA was considerably different from that in HTCA. This discrepancy could be explained by the hypothesis that VDS-35G was directed at stem cells of the HuH-7 cell population sensitively and selectively. HTCA was shown to be a useful in vitro evaluation method for drug targeting.     

Natural and Nature-Derived Products Targeting Human Coronaviruses

The ongoing pandemic of severe acute respiratory syndrome (SARS), caused by the SARS-CoV-2 human coronavirus (HCoV), has brought the international scientific community before a state of emergency that needs to be addressed with intensive research for the discovery of pharmacological agents with antiviral activity. Potential antiviral natural products (NPs) have been discovered from plants of the global biodiversity, including extracts, compounds and categories of compounds with activity against several viruses of the respiratory tract such as HCoVs. However, the scarcity of natural products (NPs) and small-molecules (SMs) used as antiviral agents, especially for HCoVs, is notable. This is a review of 203 publications, which were selected using PubMed/MEDLINE, Web of Science, Scopus, and Google Scholar, evaluates the available literature since the discovery of the first human coronavirus in the 1960s; it summarizes important aspects of structure, function, and therapeutic targeting of HCoVs as well as NPs (19 total plant extracts and 204 isolated or semi-synthesized pure compounds) with anti-HCoV activity targeting viral and non-viral proteins, while focusing on the advances on the discovery of NPs with anti-SARS-CoV-2 activity, and providing a critical perspective.     

Hybrid Polymeric Systems for Nano-Selective Counter Intervention in Virus Life Cycle

Self assembly of viral biopolymers to nano-complexes forming virions during virus delivery from infected cell and reverse disintegration to virus entry into new cells play a crucial role in viral life cycle and in viral diseases. Therefore artificial instruments for selective counter intervention into these processes are dramatically required for the high effective antiviral protection. Hybrid macromolecular systems (HMS) rationally integrating heterogeneous structure-functional factors for selective recognition - inhibition of viruses (nano-objects) without detriment for cells (micro-objects) can become a molecular basis for cardinal progress in this area. Here we discuss approaches to design and current experimental results of synthesis, and antiviral selectivity evaluations of the HMS, based on combinations of polyelectrolyte-grafted components constructed on principles of mimicry and/or complementarity to viral targets or virus-sensitive cell receptors. Particularly, the HMS generations strongly inhibiting the human immunodeficiency virus (HIV) were created as platform to novel drug development against HIV/AIDS and other sexually transmitted infections.     

Pharmacophore-Based Virtual Screening,Quantum Mechanics Calculations,and Molecular Dynamics Simulation Approaches Identified Potential Natural Antiviral Drug Candidates against MERS-CoV S1-NTD

Middle East respiratory syndrome coronavirus (MERS-CoV) is a highly infectious zoonotic virus first reported into the human population in September 2012 on the Arabian Peninsula. The virus causes severe and often lethal respiratory illness in humans with an unusually high fatality rate. The N-terminal domain (NTD) of receptor-binding S1 subunit of coronavirus spike (S) proteins can recognize a variety of host protein and mediates entry into human host cells. Blocking the entry by targeting the S1-NTD of the virus can facilitate the development of effective antiviral drug candidates against the pathogen. Therefore, the study has been designed to identify effective antiviral drug candidates against the MERS-CoV by targeting S1-NTD. Initially, a structure-based pharmacophore model (SBPM) to the active site (AS) cavity of the S1-NTD has been generated, followed by pharmacophore-based virtual screening of 11,295 natural compounds. Hits generated through the pharmacophore-based virtual screening have re-ranked by molecular docking and further evaluated through the ADMET properties. The compounds with the best ADME and toxicity properties have been retrieved, and a quantum mechanical (QM) based density-functional theory (DFT) has been performed to optimize the geometry of the selected compounds. Three optimized natural compounds, namely Taiwanhomoflavone B (Amb23604132), 2,3-Dihydrohinokiflavone (Amb23604659), and Sophoricoside (Amb1153724), have exhibited substantial docking energy >−9.00 kcal/mol, where analysis of frontier molecular orbital (FMO) theory found the low chemical reactivity correspondence to the bioactivity of the compounds. Molecular dynamics (MD) simulation confirmed the stability of the selected natural compound to the binding site of the protein. Additionally, molecular mechanics generalized born surface area (MM/GBSA) predicted the good value of binding free energies (ΔG bind) of the compounds to the desired protein. Convincingly, all the results support the potentiality of the selected compounds as natural antiviral candidates against the MERS-CoV S1-NTD.     

Epitopes based drug design for dengue virus envelope protein: A computational approach

Dengue virus (DENV) has emerged as a rapidly spreading epidemic throughout the tropical and subtropical regions around the globe. No suitable drug has been designed yet to fight against DENV, therefore, the need for safe and effective antiviral drug has become imperative. The envelope protein of DENV is responsible for mediating the fusion process between viral and host membranes. This work reports an in silico approach to target B and T cell epitopes for dengue envelope protein inhibition. A conserved region “QHGTI” in B and T cell epitopes of dengue envelope glycoprotein was confirmed to be valid for targeting by visualizing its interactions with the host cell membrane TIM-1 protein which acts as a receptor for serotype 2 and 3. A reverse pharmacophore mapping approach was used to generate a seven featured pharmacophore model on the basis of predicted epitope. This pharmacophore model as a 3D query was used to virtually screen a chemical compounds dataset “Chembridge”. A total of 1010 compounds mapped on the developed pharmacophore model. These retrieved hits were subjected to filtering via Lipinski’s rule of five, as a result 442 molecules were shortlisted for further assessment using molecular docking. Finally, 14 hits of different structural properties having interactions with the active site residues of dengue envelope glycoprotein were selected as lead candidates. These structurally diverse lead candidates have strong likelihood to act as further starting structures in the development of novel and potential drugs for the treatment of dengue fever.     

Development and Effects of Influenza Antiviral Drugs

Influenza virus is a highly contagious zoonotic respiratory disease that causes seasonal outbreaks each year and unpredictable pandemics occasionally with high morbidity and mortality rates, posing a great threat to public health worldwide. Besides the limited effect of vaccines, the problem is exacerbated by the lack of drugs with strong antiviral activity against all flu strains. Currently, there are two classes of antiviral drugs available that are chemosynthetic and approved against influenza A virus for prophylactic and therapeutic treatment, but the appearance of drug-resistant virus strains is a serious issue that strikes at the core of influenza control. There is therefore an urgent need to develop new antiviral drugs. Many reports have shown that the development of novel bioactive plant extracts and microbial extracts has significant advantages in influenza treatment. This paper comprehensively reviews the development and effects of chemosynthetic drugs, plant extracts, and microbial extracts with influenza antiviral activity, hoping to provide some references for novel antiviral drug design and promising alternative candidates for further anti-influenza drug development.     

In Vitro Antiviral Activity of α-Mangostin against Dengue Virus Serotype-2 (DENV-2)

Dengue virus (DENV), a member of the family Flaviviridae, is a threat for global health as it infects more than 100 million people yearly. Approved antiviral therapies or vaccines for the treatment or prevention of DENV infections are not available. In the present study, natural compounds were screened for their antiviral activity against DENV by in vitro cell line-based assay. α-Mangostin, a xanthanoid, was observed to exert antiviral activity against DENV-2 under pre-, co- and post-treatment testing conditions. The antiviral activity was determined by foci forming unit (FFU) assay, quantitative RT-PCR and cell-based immunofluorescence assay (IFA). A complete inhibition of DENV-2 was observed at 8 µM under the co-treatment condition. The possible inhibitory mechanism of α-Mangostin was also determined by docking studies. The molecular docking experiments indicate that α-Mangostin can interact with multiple DENV protein targets such as the NS5 methyltransferase, NS2B-NS3 protease and the glycoprotein E. The in vitro and in silico findings suggest that α-Mangostin possesses the ability to suppress DENV-2 production at different stages of its replication cycle and might act as a prophylactic/therapeutic agent against DENV-2.     

The anti-HIV potential of imidazole,oxazole and thiazole hybrids: A mini-review

Human immunodeficiency virus (HIV) especially HIV-1 infection and its progression to acquired immune deficiency syndrome (AIDS) remains a significant global health challenge. The advent of the highly active antiretroviral therapy (HAART) has greatly extended the life expectancy of patients living with HIV, but it has become evident that long-term HAART will not eliminate the HIV reservoir and cure the infection. Moreover, the drug resistance and undesirable side effects hamper efficacious therapy, creating an urgent need to develop novel, more effective and less toxic anti-HIV therapeutics. Imidazole, oxazole and thiazole with two heteroatoms at meta-position of five-membered rings are fascinating structures and constitute an important class of heterocycles in drug discovery. Their derivatives could exert the anti-HIV activity through diverse mechanisms and possess promising antiviral activity against both drug-sensitive and drug-resistant HIV strains. This review summarizes the research progress made regarding the anti-HIV potential of imidazole, oxazole and thiazole hybrids, and the structure–activity relationships (SARs) are also discussed to facilitate further rational design of more effective candidates, covering articles published from 2012 to 2022.     

Biomedical application of responsive ‘smart’ electrospun nanofibers in drug delivery system: A minireview

Electrospinning is a versatile method for producing continuous nanofibers. It has since become an easy and cost-effective technique in the manufacturing process and drawn keen interests in most biomedical field applications. Nanofibers have garnered great attention in nanomedicine due to their resemblance with the extracellular matrix (ECM). Like nanoparticles, its unique characteristics of higher surface-to-volume ratio and the tunability of the polymers utilizing nanofiber have increased the efficiency in encapsulation and drug-loading capabilities. Smart or “stimuli-responsive” polymers have shown particular fascination in controlled release, where their ability to react to minor changes in the environment, such as temperature, pH, electric field, light, or magnetic field, distinguishes them as intelligent. Polymers are a popular material for the design of drug delivery carriers; consequently, various types of drugs, including antiviral, proteins, antibiotics, DNA and RNA, are successfully encapsulated in the pH-dependent nanofibers with smart polymers which is a polymer that can respond to change such as pH change, temperature. In this minireview, we discuss applications of smart electrospun pH-responsive nanofibers in the emerging biomedical developments which includes cancer drug targeting, oral controlled release, wound healing and vaginal drug delivery.     

Silver nanoparticles as potential antiviral agents

Virus infections pose significant global health challenges, especially in view of the fact that the emergence of resistant viral strains and the adverse side effects associated with prolonged use continue to slow down the application of effective antiviral therapies. This makes imperative the need for the development of safe and potent alternatives to conventional antiviral drugs. In the present scenario, nanoscale materials have emerged as novel antiviral agents for the possibilities offered by their unique chemical and physical properties. Silver nanoparticles have mainly been studied for their antimicrobial potential against bacteria, but have also proven to be active against several types of viruses including human imunodeficiency virus, hepatitis B virus, herpes simplex virus, respiratory syncytial virus, and monkey pox virus. The use of metal nanoparticles provides an interesting opportunity for novel antiviral therapies. Since metals may attack a broad range of targets in the virus there is a lower possibility to develop resistance as compared to conventional antivirals. The present review focuses on the development of methods for the production of silver nanoparticles and on their use as antiviral therapeutics against pathogenic viruses.     

Progress in the Application of Nanoparticles and Graphene as Drug Carriers and on the Diagnosis of Brain Infections

The blood–brain barrier (BBB) is the protective sheath around the brain that protects the sensitive microenvironments of the brain. However, certain pathogens, viruses, and bacteria disrupt the endothelial barrier and cause infection and hence inflammation in meninges. Macromolecular therapeutics are unable to cross the tight junctions, thereby limiting their bioavailability in the brain. Recently, nanotechnology has brought a revolution in the field of drug delivery in brain infections. The nanostructures have high targeting accuracy and specificity to the receptors in the case of active targeting, which have made them the ideal cargoes to permeate across the BBB. In addition, nanomaterials with biomimetic functions have been introduced to efficiently cross the BBB to be engulfed by the pathogens. This review focuses on the nanotechnology-based drug delivery approaches for exploration in brain infections, including meningitis. Viruses, bacteria, fungi, or, rarely, protozoa or parasites may be the cause of brain infections. Moreover, inflammation of the meninges, called meningitis, is presently diagnosed using laboratory and imaging tests. Despite attempts to improve diagnostic instruments for brain infections and meningitis, due to its complicated and multidimensional nature and lack of successful diagnosis, meningitis appears almost untreatable. Potential for overcoming the difficulties and limitations related to conventional diagnostics has been shown by nanoparticles (NPs). Nanomedicine now offers new methods and perspectives to improve our knowledge of meningitis and can potentially give meningitis patients new hope. Here, we review traditional diagnosis tools and key nanoparticles (Au-NPs, graphene, carbon nanotubes (CNTs), QDs, etc.) for early diagnosis of brain infections and meningitis.