Novel non-HAP class A HBV capsid assembly modulators have distinct in vitro and in vivo profiles.

IMPORTANCE: Chronic hepatitis B is the most important cause of liver cancer worldwide and affects more than 290 million people. Current treatments are mostly suppressive and rarely lead to a cure. Therefore, there is a need for novel and curative drugs that target the host or the causative agent, hepatitis B virus itself. Capsid assembly modulators are an interesting class of antiviral molecules that may one day become part of curative treatment regimens for chronic hepatitis B. Here we explore the characteristics of a particularly interesting subclass of capsid assembly modulators. These so-called non-HAP CAM-As have intriguing properties in cell culture but also clear virus-infected cells from the mouse liver in a gradual and sustained way. We believe they represent a considerable improvement over previously reported molecules and may one day be part of curative treatment combinations for chronic hepatitis B.

Consequences of the first and second COVID-19 wave on kidney transplant recipients at a large Indian transplant centre.

BACKGROUND: There is a scarcity of data comparing the consequences of first and second COVID-19 waves on kidney transplant recipients (KTRs) in India. METHODS: We conducted a single-centre retrospective study of 259 KTRs with COVID-19 to compare first wave (March 15-December 31 2020, n = 157) and second wave (April 1-May 31 2021, n = 102). RESULTS: KTRs during second wave were younger (43 vs. 40 years; p-value .04) and also included paediatric patients (0 vs. 5.9%; p-value .003). Symptoms were milder during the second wave (45 vs. 62.7%; p-value .007); COVID-19 positive patients had less frequent cough (32 vs. 13.8%; p-value .001), fever was less frequent (58 vs. 37%; p-value .001), and we observed fewer co-morbidities (11 vs. 20.6%; p-value .04). The percentages of neutrophils (77 vs. 83%; p-value .001) and serum ferritin (439 vs. 688; p-value .0006) were higher during second wave, while lymphocyte counts were reduced (20 vs. 14%; p-value .0001). Hydroxychloroquine (11 vs. 0%; p-value .0001) and tocilizumab (7 vs. 0%; p-value .004) were more frequently prescribed during first wave, while utilization of dexamethasone (6 vs. 27%; p-value .0001) and remdesivir (47 vs. 65%; p-value .03) increased during the second wave. Mucormycosis (1.3 vs. 10%; p-value .01) and ICU admissions (20 vs. 37.2%; p-value .002) were more frequent during second wave. The 28-day mortality rate (9.6 vs. 10%; p-value 1) was not different. CONCLUSIONS: There has been a different clinical spectrum of COVID-19 amongst KTR with similar mortality between the two waves at a large Indian transplant centre.

Recent advances in management of COVID-19: A review.

The coronavirus disease 2019 (COVID-19) pandemic caused and is still causing significant mortality and economic consequences all over the globe. As of today, there are three U.S Food and Drug administration (FDA) approved vaccines, Pfizer-BioNTech, Moderna and Janssen COVID-19 vaccine. Also, the antiviral drug remdesivir and two combinations of monoclonal antibodies are authorized for Emergency use (EUA) in certain patients. Furthermore, baricitinib was approved in Japan (April 23, 2021). Despite available vaccines and EUA, pharmacological therapy for the prevention and treatment of COVID-19 is still highly required. There are several ongoing clinical trials investigating the efficacy of clinically available drugs in treating COVID-19. In this study, selected novel pharmacological agents for the possible treatment of COVID-19 will be discussed. Point of discussion will cover mechanism of action, supporting evidence for safety and efficacy and reached stage in development. Drugs were classified into three classes according to the phase of viral life cycle they target. Phase I, the early infective phase, relies on supportive care and symptomatic treatment as needed. In phase II, the pulmonary phase, treatment aims at inhibiting viral entry or replication. Drugs used during this phase are famotidine, monoclonal antibodies, nanobodies, ivermectin, remdesivir, camostat mesylate and other antiviral agents. Finally, phase III, the hyper-inflammatory phase, tocilizumab, dexamethasone, selective serotonin reuptake inhibitors (SSRI), and melatonin are used. The aim of this study is to summarize current findings and suggest gaps in knowledge that can influence future COVID-19 treatment study design.

Protease inhibitor-based direct-acting antivirals are associated with increased risk of aminotransferase elevations but not hepatic dysfunction or decompensation.

BACKGROUND & AIMS: Cases of acute liver injury (ALI) have been reported among chronic HCV-infected patients receiving protease inhibitor (PI)-based direct-acting antiviral (DAA) regimens, but no analyses have compared the risk of ALI in patients receiving PI- vs. non-PI-based DAAs. Thus, we compared the risk of 3 ALI outcomes between patients (by baseline Fibrosis-4 [FIB-4] group) receiving PI-based or non-PI-based DAAs. METHODS: We conducted a cohort study of 18,498 patients receiving PI-based DAA therapy (paritaprevir/ritonavir/ombitasvir±dasabuvir, elbasvir/grazoprevir, glecaprevir/pibrentasvir) matched 1:1 on propensity score to those receiving non-PI-based DAAs (sofosbuvir/ledipasvir, sofosbuvir/velpatasvir) in the 1945-1965 Veterans Birth Cohort (2014-2019). During exposure to DAA therapy, we determined development of: i) alanine aminotransferase (ALT) >200 U/L, ii) severe hepatic dysfunction (coagulopathy with hyperbilirubinemia), and iii) hepatic decompensation. We used Cox regression to determine hazard ratios (HRs) with 95% CIs for each ALI outcome within groups defined by baseline FIB-4 (≤3.25; >3.25). RESULTS: Among patients with baseline FIB-4 ≤3.25, those receiving PIs had a higher risk of ALT >200 U/L (HR 3.98; 95% CI 2.37-6.68), but not severe hepatic dysfunction (HR 0.67; 95% CI 0.19-2.39) or hepatic decompensation (HR 1.01; 95% CI 0.29-3.49), compared to those receiving non-PI-based regimens. For those with baseline FIB-4 >3.25, those receiving PIs had a higher risk of ALT >200 U/L (HR, 2.15; 95% CI 1.09-4.26), but not severe hepatic dysfunction (HR, 1.23 [0.64-2.38]) or hepatic decompensation (HR, 0.87; 95% CI 0.41-1.87), compared to those receiving non-PI-based regimens CONCLUSION: While risk of incident ALT elevations was increased in those receiving PI-based DAAs in both FIB-4 groups, the risk of severe hepatic dysfunction and hepatic decompensation did not differ between patients receiving PI- or non-PI-based DAAs in either FIB-4 group. LAY SUMMARY: Cases of liver injury have been reported among patients treated with protease inhibitor-based direct-acting antivirals for hepatitis C infection, but it is not clear if the risk of liver injury among people starting these drugs is increased compared to those starting non-protease inhibitor-based therapy. In this study, patients receiving protease inhibitor-based treatment had a higher risk of liver inflammation than those receiving a non-protease inhibitor-based treatment, regardless of the presence of pre-treatment advanced liver fibrosis/cirrhosis. However, the risk of severe liver dysfunction and decompensation were not higher for patients treated with protease inhibitor-based regimens.

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.

Nanoparticles as a novel and promising antiviral platform in veterinary medicine.

Traditional veterinary virus vaccines, such as inactivated and live-attenuated vaccines, have achieved tremendous success in controlling many viral diseases of livestock and chickens worldwide. However, many recent viral outbreaks caused by different emerging and re-emerging viruses continue to be reported annually worldwide. It is therefore necessary to develop new control regimens. Nanoparticle research has received considerable attention in the last two decades as a promising platform with significant success in veterinary medicine, replacing traditional viral vector vaccines. However, the field of nanoparticle applications is still in its initial phase of growth. Here, we discuss various preparation methods, characteristics, physical properties, antiviral effects, and pharmacokinetics of well-developed nanoparticles and the potential of nanoparticles or nano-vaccines as a promising antiviral platform for veterinary medicine.

Active Learning and the Potential of Neural Networks Accelerate Molecular Screening for the Design of a New Molecule Effective against SARS-CoV-2.

A global pandemic has emerged following the appearance of the new severe acute respiratory virus whose official name is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), strongly affecting the health sector as well as the world economy. Indeed, following the emergence of this new virus, despite the existence of a few approved and known effective vaccines at the time of writing this original study, a sense of urgency has emerged worldwide to discover new technical tools and new drugs as soon as possible. In this context, many studies and researches are currently underway to develop new tools and therapies against SARS CoV-2 and other viruses, using different approaches. The 3-chymotrypsin (3CL) protease, which is directly involved in the cotranslational and posttranslational modifications of viral polyproteins essential for the existence and replication of the virus in the host, is one of the coronavirus target proteins that has been the subject of these extensive studies. Currently, the majority of these studies are aimed at repurposing already known and clinically approved drugs against this new virus, but this approach is not really successful. Recently, different studies have successfully demonstrated the effectiveness of artificial intelligence-based techniques to understand existing chemical spaces and generate new small molecules that are both effective and efficient. In this framework and for our study, we combined a generative recurrent neural network model with transfer learning methods and active learning-based algorithms to design novel small molecules capable of effectively inhibiting the 3CL protease in human cells. We then analyze these small molecules to find the correct binding site that matches the structure of the 3CL protease of our target virus as well as other analyses performed in this study. Based on these screening results, some molecules have achieved a good binding score close to -18 kcal/mol, which we can consider as good potential candidates for further synthesis and testing against SARS-CoV-2.

Proposal of novel natural inhibitors of severe acute respiratory syndrome coronavirus 2 main protease: Molecular docking and ab initio fragment molecular orbital calculations.

This paper proposes natural drug candidate compounds for the treatment of coronavirus disease 2019 (COVID-19). We investigated the binding properties between the compounds in the Moringa oleifera plant and the main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 using molecular docking and ab initio fragment molecular orbital calculations. Among the 12 compounds, niaziminin was found to bind the strongest to Mpro. We furthermore proposed novel compounds based on niaziminin and investigated their binding properties to Mpro. The results reveal that the introduction of a hydroxyl group into niaziminin enhances its binding affinity to Mpro. These niaziminin derivatives can be promising candidate drugs for the treatment of COVID-19.

Clinical outcome and the role of antivirals in congenital cytomegalovirus infection.

Congenital cytomegalovirus (cCMV) infection is a leading cause of hearing loss and neurological disabilities in children worldwide. Although a minority of infants with cCMV will have symptoms at a birth, these children are at high risk of long-term sequelae. Most infants with cCMV have no clinical signs at birth (asymptomatic), but 10-15% will develop hearing loss. The diagnosis of cCMV relies on detection of the virus from urine or saliva within the first three weeks of life, with saliva PCR being the preferred method due to ease of collection and high sensitivity of the assay. Measures to prevent mother-to-child transmission of CMV are limited, and antiviral therapy with valganciclovir for 6 months is the standard of care for infants with symptomatic cCMV. As more infants with cCMV are being identified through newborn screening, studies are urgently needed to address antiviral treatment in asymptomatic infants and the implementation of prevention strategies to prevent fetal infection. This article is part of the symposium "New drugs and vaccines for DNA virus infections: a symposium in memory of Mark Prichard."

Classification, structure and mechanism of antiviral polysaccharides derived from edible and medicinal fungus.

The deficiency of chemical-synthesized antiviral drugs when applied in clinical therapy, such as drug resistance, and the lack of effective antiviral drugs to treat some newly emerging virus infections, such as COVID-19, promote the demand of novelty and safety anti-virus drug candidate from natural functional ingredient. Numerous studies have shown that some polysaccharides sourcing from edible and medicinal fungus (EMFs) exert direct or indirect anti-viral capacities. However, the internal connection of fungus type, polysaccharides structural characteristics, action mechanism was still unclear. Herein, our review focus on the two aspects, on the one hand, we discussed the type of anti-viral EMFs and the structural characteristics of polysaccharides to clarify the structure-activity relationship, on the other hand, the directly or indirectly antiviral mechanism of EMFs polysaccharides, including virus function suppression, immune-modulatory activity, anti-inflammatory activity, regulation of population balance of gut microbiota have been concluded to provide a comprehensive theory basis for better clinical utilization of EMFs polysaccharides as anti-viral agents.

Antivirals Targeting the Surface Glycoproteins of Influenza Virus: Mechanisms of Action and Resistance.

Hemagglutinin and neuraminidase, which constitute the glycoprotein spikes expressed on the surface of influenza A and B viruses, are the most exposed parts of the virus and play critical roles in the viral lifecycle. As such, they make prominent targets for the immune response and antiviral drugs. Neuraminidase inhibitors, particularly oseltamivir, constitute the most commonly used antivirals against influenza viruses, and they have proved their clinical utility against seasonal and emerging influenza viruses. However, the emergence of resistant strains remains a constant threat and consideration. Antivirals targeting the hemagglutinin protein are relatively new and have yet to gain global use but are proving to be effective additions to the antiviral repertoire, with a relatively high threshold for the emergence of resistance. Here we review antiviral drugs, both approved for clinical use and under investigation, that target the influenza virus hemagglutinin and neuraminidase proteins, focusing on their mechanisms of action and the emergence of resistance to them.

Development of Interferon-Free, Direct-Acting Antivirals Treatment for Japanese Patients with Chronic Hepatitis C Infection and Chronic Kidney Disease.

Chronic hepatitis C virus (HCV) infection can progress to liver cirrhosis and hepatocellular carcinoma. Interferon-based treatment was previously the only antiviral therapy for chronic hepatitis C infection; however, development of interferon-free, direct-acting antivirals, in 2014, markedly improved treatment efficacy and safety. Treatment indications were expanded to include elderly adults, patients with advanced liver fibrosis, and patients with chronic hepatitis C infection complicated by chronic kidney disease, for whom antiviral therapy had been difficult or contraindicated. The median age of patients with chronic HCV infection in Japan is 70 years, older than in other countries. Because diminished renal function is common in elderly adults, a safe and effective treatment for chronic hepatitis C complicated by chronic kidney disease has been expected in Japan. In addition, the HCV antibody-positive rate is higher in hemodialysis patients than in non-hemodialysis patients in Japan. Numerous studies have reported that direct-acting antivirals are safe and effective for hepatitis C patients on hemodialysis. This review summarizes treatments available in Japanese clinical practice for patients with chronic HCV infection complicated by chronic kidney disease, including hemodialysis patients.

An update review of emerging small-molecule therapeutic options for COVID-19.

The SARS-CoV-2 outbreak and pandemic that began near the end of 2019 has posed a challenge to global health. At present, many candidate small-molecule therapeutics have been developed that can inhibit both the infection and replication of SARS-CoV-2 and even potentially relieve cytokine storms and other related complications. Meanwhile, host-targeted drugs that inhibit cellular transmembrane serine protease (TMPRSS2) can prevent SARS-CoV-2 from entering cells, and its combination with chloroquine and dihydroorotate dehydrogenase (DHODH) inhibitors can limit the spread of SARS-CoV-2 and reduce the morbidity and mortality of patients with COVID-19. The present article provides an overview of these small-molecule therapeutics based on insights from medicinal chemistry research and focuses on RNA-dependent RNA polymerase (RdRp) inhibitors, such as the nucleoside analogues remdesivir, favipiravir and ribavirin. This review also covers inhibitors of 3C-like protease (3CLpro), papain-like protease (PLpro) and other potentially innovative active ingredient molecules, describing their potential targets, activities, clinical status and side effects.

Effective drugs used to combat SARS-CoV-2 infection and the current status of vaccines.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a causal factor of the coronavirus disease 2019 (COVID-19). Drug repurposing, portraying patented drugs as a successful drug development technique, could shorten the period and minimize costs relative to de novo drug exploration. Recently several drugs have been used as anti-SARS-CoV-2 such as Remdesivir, Favipiravir, Hydroxychloroquine, Azithromycin, Lopinavir/Ritonavir, Nafamostat mesylate and so on. Despite such efforts, there is currently no successful broad-spectrum antiviral countermeasures to combat SARS-CoV-2 or possibly potential CoVs pandemic. Therefore it is desperately important to recognize and test widely efficient, reliable anti-CoV therapies now and in the future. Remdesivir and Favipiravir were more promising despite having side effects; it had prominent efficacy and efficiency while still not yet approved as the official anti-viral drug for SARS CoV-2. In this review, we summarizes the current drug and vaccine discovery status against SARS-CoV-2, predicting that these efforts will help create effective drugs and vaccines for SARS-CoV-2.

SARS-CoV-2: From the pathogenesis to potential anti-viral treatments.

INTRODUCTION: The world is witnessing the spread of one of the members of Coronaviruses (CoVs) family, called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the 21st century. Considering the short time spent after its prevalence, limited information is known about the effect of the virus mechanism on different organs of the body; meanwhile the lack of specific treatment and vaccine for this virus has exposed millions of people to a big challenge. AREAS COVERED: The review article aims to describe the general and particular characteristics of CoVs, their classification, genome structure, host cell infection, cytokine storm, anti-viral treatments, and inhibition of COVID-19-related ER-mitochondrial stress. In addition, it refers to drugs such as Chloroquine/Hydroxychloroquine, Lopinavir/Ritonavir, darunavir, ribavirin, remdesivir, and favipiravir, which have undergone clinical trials for coronavirus disease 2019 (COVID-19) treatment. This analysis was derived from an extensive scientific literature search including Pubmed, ScienceDirect, and Google Scholar performed. EXPERT OPINION: The effectiveness rate and complications of these drugs can reveal new insights into the potential therapeutic goals for the disease. Moreover, lifestyle change can effectively prevent SARS-CoV-2 infection.

Why do we lack a specific magic anti-COVID-19 drug? Analyses and solutions.

The Coronavirus 2019 (COVID-19) pandemic represents the greatest worldwide public health crisis of recent times. The lack of proven effective therapies means that COVID-19 rages relatively unchecked. Current anti-COVID-19 pharmacotherapies are drugs originally designed for other diseases, and administered orally or intravascularly. Thus, they can have various adverse effects. A specific anti-Coronavirus drug should not only target the virus per se, but also treat the related respiratory and cardiovascular symptoms. Here, we examine the advantages and disadvantages of current anti-COVID-19 pharmacotherapies, and analyze the reasons why in the era of big data we have not yet established specific coronavirus therapies and related technical bottlenecks. Finally, we present our design of a novel nebulized S-nitrosocaptopril that is under development for targeting both coronaviruses and their related symptoms.

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.

Nonalcoholic Fatty Liver Disease Risk Factors Affect Liver-Related Outcomes After Direct-Acting Antiviral Treatment for Hepatitis C.

INTRODUCTION: In hepatitis C (HCV) patients, obesity and/or diabetes may increase the risk of liver-related outcomes. We aimed to determine whether diabetes and/or obesity are associated with adverse outcomes in direct-acting antiviral (DAA)-treated HCV patients. METHODS: We conducted a retrospective study of 33,003 HCV-infected, DAA-treated Veterans between 2013 and 2015. Body mass index was used to categorize patients into underweight (< 18.5 kg/m2), normal weight (18.5 to < 25 kg/m2), overweight (25 to < 30 kg/m2), obesity I (30 to < 35 kg/m2), and obesity II-III (> 35 kg/m2). Diabetes was defined by ICD-9/10 codes in association with hemoglobin A1c > 6.5% or medication prescriptions. Patients were followed from 180 days post-DAA initiation until 2/14/2019 to assess for development of cirrhosis, decompensations, hepatocellular carcinoma (HCC), and death. Multivariable Cox proportional hazards regression models were used to determine the association between diabetes and/or obesity and outcomes. RESULTS: During a mean follow-up of 3 years, 10.1% patients died, 5.0% were newly diagnosed with cirrhosis, 4.7% had a decompensation and 4.0% developed HCC. Diabetes was associated with an increased risk of mortality (AHR = 1.25, 95% CI 1.10-1.42), cirrhosis (AHR = 1.31, 95% CI 1.16-1.48), decompensation (AHR = 1.74, 95% CI 1.31-2.31), and HCC (AHR = 1.32, 95% CI 1.01-1.72) among patients without baseline cirrhosis. Compared to normal-weight persons, obese persons had a higher risk of cirrhosis, but overweight and obese persons had lower risk of mortality and HCC. CONCLUSIONS: In this large DAA-treated Veterans cohort, pre-DAA diabetes increases mortality and liver-related events independent of SVR. Continued vigilance is warranted in patients with diabetes despite SVR. Elevated BMI categories appear to have improved outcomes, although further studies are needed to understand those associations.

Cardiovascular Complications of COVID-19: Pharmacotherapy Perspective.

Coronavirus disease of 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is spreading rapidly the world over. The disease was declared "pandemic" by the World Health Organization. An approved therapy for patients with COVID-19 has yet to emerge; however, there are some medications used in the treatment of SARS-CoV-2 infection globally including hydroxychloroquine, remdesivir, dexamethasone, protease inhibitors, and anti-inflammatory agents. Patients with underlying cardiovascular disease are at increased risk of mortality and morbidity from COVID-19. Moreover, patients with chronic stable states and even otherwise healthy individuals might sustain acute cardiovascular problems due to COVID-19 infection. This article seeks to review the latest evidence with a view to explaining possible pharmacotherapies for the cardiovascular complications of COVID-19 including acute coronary syndrome, heart failure, myocarditis, arrhythmias, and venous thromboembolism, as well as possible interactions between these medications and those currently administered (or under evaluation) in the treatment of COVID-19.