COVID-19 challenges and its therapeutics.

COVID-19, an infectious disease, has emerged as one of the leading causes of death worldwide, making it one of the severe public health issues in recent decades. nCoV, the novel SARS coronavirus that causes COVID-19, has brought together scientists in the quest for possible therapeutic and preventive measures. The development of new drugs to manage COVID-19 effectively is a challenging and time-consuming process, thus encouraging extensive investigation of drug repurposing and repositioning candidates. Several medications, including remdesivir, hydroxychloroquine, chloroquine, lopinavir, favipiravir, ribavirin, ritonavir, interferons, azithromycin, capivasertib and bevacizumab, are currently under clinical trials for COVID-19. In addition, several medicinal plants with considerable antiviral activities are potential therapeutic candidates for COVID-19. Statistical data show that the pandemic is yet to slow down, and authorities are placing their hopes on vaccines. Within a short period, four types of vaccines, namely, whole virus, viral vector, protein subunit, and nucleic acid (RNA/DNA), which can confer protection against COVID-19 in different ways, were already in a clinical trial. SARS-CoV-2 variants spread is associated with antibody escape from the virus Spike epitopes, which has grave concerns for viral re-infection and even compromises the effectiveness of the vaccines. Despite these efforts, COVID-19 treatment is still solely based on clinical management through supportive care. We aim to highlight the recent trends in COVID-19, relevant statistics, and clinical findings, as well as potential therapeutics, including in-line treatment methods, preventive measures, and vaccines to combat the prevalence of COVID-19.

Natural products for COVID-19 prevention and treatment regarding to previous coronavirus infections and novel studies.

Recently, the novel life-threatening coronavirus infection (COVID-19) was reported at the end of 2019 in Wuhan, China, and spread throughout the world in little time. The effective antiviral activities of natural products have been proved in different studies. In this review, regarding the effective herbal treatments on other coronavirus infections, promising natural products for COVID-19 treatment are suggested. An extensive search in Google Scholar, Science Direct, PubMed, ISI, and Scopus was done with search words include coronavirus, COVID-19, SARS, MERS, natural product, herb, plant, and extract. The consumption of herbal medicine such as Allium sativum, Camellia sinensis, Zingiber officinale, Nigella sativa, Echinacea spp. Hypericum perforatum, and Glycyrrhiza glabra, Scutellaria baicalensis can improve the immune response. It seems that different types of terpenoids have promising effects in viral replication inhibition and could be introduced for future studies. Additionally, some alkaloid structures such as homoharringtonine, lycorine, and emetine have strong anti-coronavirus effects. Natural products can inhibit different coronavirus targets such as S protein (emodin, baicalin) and viral enzymes replication such as 3CLpro (Iguesterin), PLpro (Cryptotanshinone), helicase (Silvestrol), and RdRp (Sotetsuflavone). Based on previous studies, natural products can be introduced as preventive and therapeutic agents in the fight against coronavirus.

Bioactive Natural Antivirals: An Updated Review of the Available Plants and Isolated Molecules.

Viral infections and associated diseases are responsible for a substantial number of mortality and public health problems around the world. Each year, infectious diseases kill 3.5 million people worldwide. The current pandemic caused by COVID-19 has become the greatest health hazard to people in their lifetime. There are many antiviral drugs and vaccines available against viruses, but they have many disadvantages, too. There are numerous side effects for conventional drugs, and active mutation also creates drug resistance against various viruses. This has led scientists to search herbs as a source for the discovery of more efficient new antivirals. According to the World Health Organization (WHO), 65% of the world population is in the practice of using plants and herbs as part of treatment modality. Additionally, plants have an advantage in drug discovery based on their long-term use by humans, and a reduced toxicity and abundance of bioactive compounds can be expected as a result. In this review, we have highlighted the important viruses, their drug targets, and their replication cycle. We provide in-depth and insightful information about the most favorable plant extracts and their derived phytochemicals against viral targets. Our major conclusion is that plant extracts and their isolated pure compounds are essential sources for the current viral infections and useful for future challenges.

A SARS-CoV-2 protein interaction map reveals targets for drug repurposing.

A newly described coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the causative agent of coronavirus disease 2019 (COVID-19), has infected over 2.3 million people, led to the death of more than 160,000 individuals and caused worldwide social and economic disruption1,2. There are no antiviral drugs with proven clinical efficacy for the treatment of COVID-19, nor are there any vaccines that prevent infection with SARS-CoV-2, and efforts to develop drugs and vaccines are hampered by the limited knowledge of the molecular details of how SARS-CoV-2 infects cells. Here we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins that physically associated with each of the SARS-CoV-2 proteins using affinity-purification mass spectrometry, identifying 332 high-confidence protein-protein interactions between SARS-CoV-2 and human proteins. Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (of which, 29 drugs are approved by the US Food and Drug Administration, 12 are in clinical trials and 28 are preclinical compounds). We screened a subset of these in multiple viral assays and found two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the sigma-1 and sigma-2 receptors. Further studies of these host-factor-targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19.

Preclinical Antiviral Testing for Dengue Virus Infection in Mouse Models and Its Association with Clinical Studies.

At present, there is no licensed antiviral drug against dengue virus (DENV) infection. Mouse models of DENV infection have been widely used for preclinical evaluation of antivirals. However, only in a few instances so far have the data obtained from preclinical mouse model testing been associated with data from clinical studies in humans. In this Review, we focus on the antiviral drugs targeting viral replication that have been tested in animals/humans and discuss how preclinical drug evaluation in suitable mouse/animal models may be more fruitfully used to inform early phase clinical testing.

Host-Targeting Agents to Prevent and Cure Hepatitis C Virus Infection.

Chronic hepatitis C virus (HCV) infection is a major cause of liver cirrhosis and hepatocellular carcinoma (HCC) which are leading indications of liver transplantation (LT). To date, there is no vaccine to prevent HCV infection and LT is invariably followed by infection of the liver graft. Within the past years, direct-acting antivirals (DAAs) have had a major impact on the management of chronic hepatitis C, which has become a curable disease in the majority of DAA-treated patients. In contrast to DAAs that target viral proteins, host-targeting agents (HTAs) interfere with cellular factors involved in the viral life cycle. By acting through a complementary mechanism of action and by exhibiting a generally higher barrier to resistance, HTAs offer a prospective option to prevent and treat viral resistance. Indeed, given their complementary mechanism of action, HTAs and DAAs can act in a synergistic manner to reduce viral loads. This review summarizes the different classes of HTAs against HCV infection that are in preclinical or clinical development and highlights their potential to prevent HCV infection, e.g., following LT, and to tailor combination treatments to cure chronic HCV infection.

Evaluation of salidroside in vitro and in vivo genotoxicity.

It is reported that salidroside, the main component of a traditional Chinese medicine, Rhodiola rosea, has the efficacy of protecting Coxsackie virus impairment. As part of a safety evaluation on salidroside for use in the treatment of viral myocarditis, the present study evaluated potential genotoxicity of salidroside by using the standard battery of tests (i.e., bacterial reverse mutation assay, chromosomal aberrations assay, and mouse micronucleus assay) recommended by the State Food and Drug Administration of China. The results showed that salidroside was not genotoxic under the conditions of the reverse mutation assay, chromosomal aberrations assay, and mouse micronucleus assay conditions. The anticipated clinical dose seems to be smaller than the doses administered in the genotoxicity assays. With confirmation from further toxicity studies, salidroside would hopefully prove to be a safe anti-Coxsackie virus agent.

9-Arylpurines as a novel class of enterovirus inhibitors.

Here we report on a novel class of enterovirus inhibitors that can be structurally described as 9-arylpurines. These compounds elicit activity against a variety of enteroviruses in the low microM range including Coxsackie virus A16, A21, A24, Coxsackie virus B3, and echovirus 9. Structure-activity relationship (SAR) studies indicate that a chlorine or bromine atom is required at position 6 of the purine ring for antiviral activity. The most selective compounds in this series inhibited Coxsackie virus B3 replication in a dose-dependent manner with EC(50) values around 5-8 microM. No toxicity on different cell lines was observed at concentrations up to 250 microM. Moreover, no cross-resistance to TBZE-029 and TTP-8307 CVB3 resistant strains was detected.

Management of herpes zoster and postherpetic neuralgia.

Patients with herpes zoster experience severe pain and potential lasting complications such as postherpetic neuralgia, ophthalmic disease/damage, and, rarely, skin complications (eg, infection of rash area). Treatment for acute zoster aims to accelerate healing, control pain, and, when possible, reduce the risk of complications. Early intervention with antivirals can accelerate rash healing, reduce rash severity, and reduce the risk of some complications. The addition of corticosteroids to antiviral medication may further alleviate short-term zoster pain, but is associated with an increased risk of serious adverse effects, especially among older adults. If a patient does develop postherpetic neuralgia, gabapentin, pregabalin, opioids, tricyclic antidepressants, lidocaine patch 5%, and capsaicin may all be considered as palliative treatments. For individuals with treatment-refractory postherpetic neuralgia, nonpharmacologic approaches may be considered and a pain-management specialist should be consulted. There is a need for more effective agents to treat herpes zoster and postherpetic neuralgia.

Novel and specific inhibitors of a poxvirus type I topoisomerase.

Vaccinia DNA topoisomerase (vTopo) is a prototypic pox virus family topoisomerase that shares extensive structural and mechanistic properties with the human type IB enzyme (hTopo) and is important for viral replication. Despite their far-reaching similarities, vTopo and hTopo have surprisingly distinct pharmacological properties. To further exploit these differences, we have developed recently the first high-throughput screen for vTopo, which has allowed rapid screening of a 1990-member small-molecule library for inhibitors. Using this approach, 21 compounds were identified with IC(90) values less than 10 muM, and 19 of these were also found to inhibit DNA supercoil relaxation by vTopo. Four of the most potent compounds were completely characterized and are structurally novel topo I inhibitors with efficacies at nanomolar concentrations. These inhibitors were highly specific for vTopo, showing no inhibition of the human enzyme even at 500- to 2000-fold greater concentrations. We describe a battery of efficient experiments to characterize the unique mechanisms of these vTopo inhibitors and discuss the surprising promiscuity of this enzyme to inhibition by structurally diverse small molecules.

[New medical treatment for viral conjunctivitis].

Around one million people in Japan are suffering from adenoviral conjunctivitis every year and it is recognized as one of the major pathogens of nosocomial infection. Several complications, such as corneal erosion and conjunctival pseudomembrane, are observed in some of the cases and corneal sube- pithelial opacity may bring visual impairment. Moreover, no specific anti-adenoviral agent has been discovered and an effective treatment has not been established for adenoviral infection. We have researched new medical treatment for viral conjunctivitis based on recent findings in adenoviral conjunctivitis. Firstly, anti-adenoviral activity was evaluated in vitro in agents which could possibly act as anti-adenoviral drugs. Twelve candidates, such as zalcitabin, interferon beta, etc., were selected among antiviral drugs, adenoviral receptor inhibitors, natural products and anti-inflammatory drugs. Remarkable anti-adenoviral effect was observed in zalcitabin, sanilbudine, interferon beta and anti-osteopontin peptide. Two anti-human immunodeficiency virus (HIV) drugs with anti-adenoviral activity, zalcitabin and sanilbudine, are nucleoside reverse transcriptase inhibitors, but, in contrast, non-nucleoside reverse transcriptase inhibitors and protease inhibitors were ineffective against adenovirus. Interferon beta and anti-osteopontin peptide displayed anti-adenoviral effects by absorption inhibition. Secondly, side effects caused by possible anti-adenoviral eye drops, including cidofovir whose development as eye drops against eyeball and ocular adnexa had been suspended, were analyzed in a white rabbit model. In animals given cidofovir locally, significant narrowing of lacrimal canaliculus, redness of eyelid and conjunctival injection was observed, but obstruction of the lacrimal duct was not found. Although zalcitabin and sanilbudine eye drops induced eyelid redness, no change was observed in the lacrimal route and conjunctiva. In animals treated by cidofovir, inflammation histologically suggesting mainly allergic change was observed. These results indicate that these four drugs are possible candidate for safe eye drops against adenoviral conjunctivitis. These four agents are divided into two categories, inhibitors of adenoviral replication, zalcitabin and sanilbudine; and suppressors of adenoviral infection, interferon beta and anti-osteopontin peptide. It is expected that eye drops for specific treatment of adenoviral conjunctivitis are going to be available in the near future following investigation of therapeutic effect in adenoviral infected animals and clinical trials in humans.

Systematic review and economic decision modelling for the prevention and treatment of influenza A and B.

OBJECTIVES: To establish the clinical and cost-effectiveness of amantadine, oseltamivir and zanamivir compared to standard care for the treatment and prevention of influenza. DATA SOURCES: Electronic databases. Reference lists of identified articles and key publications. Relevant trials. REVIEW METHODS: A systematic review and meta-analysis of the randomised evidence was undertaken to investigate the effectiveness of oseltamivir and zanamivir compared to standard care for treatment and prophylaxis use for influenza A and B. An additional systematic review of the effectiveness of amantadine for treatment and prophylaxis use for influenza A in children and the elderly was also undertaken. Economic decision models were constructed to examine the cost-effectiveness and cost-utility of the alternative strategies for treating and preventing influenza A and/or B. This was informed by the systematic reviews outlined above and additional sources of information where required. RESULTS: The systematic review of the treatment of influenza found that oseltamivir reduced the median duration of symptoms in the influenza positive group by 1.38 days for the otherwise healthy adult population, 0.5 day for the high-risk population, and 1.5 days for the children population. This compared to 1.26 days, 1.99 days, and 1.3 for the similar groups for inhaled zanamivir. The systematic review of the prevention of influenza found that the relative risk reduction for oseltamivir was between approximately 75 and 90% and approximately 70 and 90% for inhaled zanamivir depending on the strategy adopted and the population under consideration. For the economic model a base case was constructed that focussed primarily on the health benefits generated by shortening the period of influenza illness. This base case found that, compared to standard care, the estimated cost per quality-adjusted life year ranged from pound 6190 to pound 31,529 for healthy adults, from pound 4535 to pound 22,502 for the 'high-risk' group, from pound 6117 to pound 30,825 for children, and from pound 5057 to pound 21,781 for the residential care elderly population. The base case model included valuations of the health effects of pneumonia (and otitis media in the children's model) based on observed rates in the trials. However it does not include the cost of hospitalisations as only very limited data was available for the effects of antivirals on hospitalisation rates. As for mortality rates, deaths from influenza were rare in trials of neuraminidase inhibitors (NIs). Therefore, suitable data on mortality were not available from these sources. As avoided hospitalisation costs and avoided mortality are potentially important we also carried out sensitivity analysis that involved extrapolating the observed reductions in pneumonias in the NI trials to hospitalisations and deaths. In all four models the cost-effectiveness of NIs is substantially improved by this extrapolation. For prophylaxis, antiviral drugs were compared with vaccination as preventative strategies. In all cases the cost-effectiveness ratios for vaccination were either low or cost-saving. In the base case the cost-effectiveness of antivirals was relatively unfavourable, there were scenarios relating to the elderly residential care model where antivirals as an additional strategy could be cost-effective. CONCLUSIONS: The cost-effectiveness varies markedly between the intervention strategies and target populations. The estimate of cost effectiveness is also sensitive to variations in certain key parameters of the model, for example the proportion of all influenza-like illnesses that are influenza. The effectiveness literature that was used to inform the economic decision model spans many decades and hence great caution should be exercised when interpreting the results of indirect intervention comparisons from the model. Further randomised trials making direct comparisons would be valuable to verify the model's findings.

Clustering a large number of compounds. 3. The limits of classification.

Clustering is normally used to group items that are similar. In this application of obtaining a diverse sample from the 230,000 compounds in the National Cancer Institute Repository, we cluster to select compounds that are different from the rest, to optimize screening for new leads. With these constraints, our approach yielded many singleton clusters. We can interpret these results as evidence for a limit to classification, contrary to the customary view of chemistry as a study of classes of compounds.