Broad-Spectrum Antivirals Derived from Natural Products.

Scientific advances have led to the development and production of numerous vaccines and antiviral drugs, but viruses, including re-emerging and emerging viruses, such as SARS-CoV-2, remain a major threat to human health. Many antiviral agents are rarely used in clinical treatment, however, because of their inefficacy and resistance. The toxicity of natural products may be lower, and some natural products have multiple targets, which means less resistance. Therefore, natural products may be an effective means to solve virus infection in the future. New techniques and ideas are currently being developed for the design and screening of antiviral drugs thanks to recent revelations about virus replication mechanisms and the advancement of molecular docking technology. This review will summarize recently discovered antiviral drugs, mechanisms of action, and screening and design strategies for novel antiviral agents.

TASL, TADE, and DAROC consensus for the screening and management of hepatitis C in patients with diabetes.

Diabetes mellitus (DM) and hepatitis C virus (HCV) infection are prevalent diseases globally and emerging evidence demonstrates the bidirectional association between the two diseases. Direct-acting antivirals (DAAs) for HCV have a high treatment success rate and can significantly reduce the risks of short and long-term complications of HCV infection. However, despite the evidence of the association between diabetes and HCV and the benefits of anti-HCV treatment, previously published guidelines did not focus on the universal HCV screening for patients with diabetes and their subsequent management once confirmed as having HCV viremia. Nonetheless, screening for HCV among patients with diabetes will contribute to the eradication of HCV infection. Thus, the three major Taiwan medical associations of diabetes and liver diseases endorsed a total of 14 experts in the fields of gastroenterology, hepatology, diabetology, and epidemiology to convene and formulate a consensus statement on HCV screening and management among patients with diabetes. Based on recent studies and guidelines as well as from real-world clinical experiences, the Taiwan experts reached a consensus that provides a straightforward approach to HCV screening, treatment, and monitoring of patients with diabetes.

Crystal Structures of Inhibitor-Bound Main Protease from Delta- and Gamma-Coronaviruses.

With the spread of SARS-CoV-2 throughout the globe causing the COVID-19 pandemic, the threat of zoonotic transmissions of coronaviruses (CoV) has become even more evident. As human infections have been caused by alpha- and beta-CoVs, structural characterization and inhibitor design mostly focused on these two genera. However, viruses from the delta and gamma genera also infect mammals and pose a potential zoonotic transmission threat. Here, we determined the inhibitor-bound crystal structures of the main protease (Mpro) from the delta-CoV porcine HKU15 and gamma-CoV SW1 from the beluga whale. A comparison with the apo structure of SW1 Mpro, which is also presented here, enabled the identification of structural arrangements upon inhibitor binding at the active site. The cocrystal structures reveal binding modes and interactions of two covalent inhibitors, PF-00835231 (active form of lufotrelvir) bound to HKU15, and GC376 bound to SW1 Mpro. These structures may be leveraged to target diverse coronaviruses and toward the structure-based design of pan-CoV inhibitors.

Inhibition of Human Coronaviruses by Combinations of Host-Targeted and Direct-Acting Antivirals.

Antiviral compounds targeting cellular metabolism are part of the therapeutic arsenal to control the spread of virus infection, either as sole treatment or in combination with direct-acting antivirals (DAA) or vaccines. Here, we describe the effect of two of them, lauryl gallate (LG) and valproic acid (VPA) both exhibiting a wide antiviral spectrum, against infection by coronaviruses such as HCoV-229E, HCoV-OC43, and SARS-CoV-2. A consistent 2 to 4-log-decrease in virus yields was observed in the presence of each antiviral, with an average IC50 value of 1.6 µM for LG and 7.2 mM for VPA. Similar levels of inhibition were observed when adding the drug 1 h before adsorption, at the time of infection or 2 h after infection, supporting a postvirus entry mechanism of action. The specificity of the antiviral effect of LG against SARS-CoV-2, relative to other related compounds such as gallic acid (G) and epicatechin gallate (ECG), predicted to be better inhibitors according to in silico studies, was also demonstrated. The combined addition of LG, VPA, and remdesivir (RDV), a DAA with a proven effect against human coronaviruses, resulted in a robust synergistic effect between LG and VPA, and to a lesser extent between the other drug combinations. These findings reinforce the interest of these wide antiviral spectrum host-targeted compounds as a first line of defense against viral diseases or as a vaccine complement to minimize the gap in antibody-mediated protection evoked by vaccines, either in the case of SARS-CoV-2 or for other possible emerging viruses.

Clinician barriers, perceptions, and practices in treating patients with hepatitis C virus and substance use disorder in the United States.

The likelihood of clinicians prescribing direct-acting antiviral (DAA) therapy for patients with chronic hepatitis C virus (HCV) and substance use disorder (SUD) was assessed via a survey emailed throughout the United States to clinicians (physicians and advanced practice providers) in gastroenterology, hepatology, and infectious disease specialties. Clinicians' perceived barriers and preparedness and actions associated with current and future DAA prescribing practices of HCV-infected patients with SUD were assessed. Of 846 clinicians presumably receiving the survey, 96 completed and returned it. Exploratory factor analyses of perceived barriers indicated a highly reliable (Cronbach alpha = 0.89) model with five factors: HCV stigma and knowledge, prior authorization requirements, and patient- clinician-, and system-related barriers. In multivariable analyses, after controlling for covariates, patient-related barriers (P < 0.01) and prior authorization requirements (P < 0.01) were negatively associated with the likelihood of prescribing DAAs. Exploratory factor analyses of clinician preparedness and actions indicated a highly reliable (Cronbach alpha = 0.75) model with three factors: beliefs and comfort level; action; and perceived limitations. Clinician beliefs and comfort levels were negatively associated with the likelihood of prescribing DAAs (P = 0.01). Composite scores of barriers (P < 0.01) and clinician preparedness and actions (P < 0.05) were also negatively associated with the intent to prescribe DAAs. Conclusion: These findings underscore the importance of addressing patient-related barriers and prior authorization requirements-significant problematic barriers-and improving clinicians' beliefs (e.g., medication-assisted therapy should be prescribed before DAAs) and comfort levels for treating patients with HCV and SUD to enhance treatment access for patients with both HCV and SUD.

Hepatitis B Virus Reactivation Associated With Therapeutic Interventions.

Hepatitis B virus (HBV) reactivation associated with various therapeutic interventions is an important cause of morbidity and mortality in patients with current or resolved HBV infection. Because no curative treatment for HBV infection is yet available, there are many individuals at risk for HBV reactivation in the general population. Populations at risk for HBV reactivation include patients who are currently infected with HBV or who have been exposed to HBV in the past. HBV reactivation and its potential consequences is a concern when these populations are exposed to anti-cancer chemotherapy, immunosuppressive or immunomodulatory therapies for the management of various malignancies, rheumatologic diseases, inflammatory bowel disease, or solid-organ or hematologic stem cell transplantation. Accordingly, it has become important to understand the basics of HBV reactivation and the mechanisms by which certain therapies are more susceptible to HBV reactivation. This review aims to raise the awareness of HBV reactivation and to understand the mechanisms and the risks of HBV reactivation in various clinical settings.

Potential interventions to support HCV treatment uptake among HIV co-infected people in Canada: Perceptions of patients and health care providers.

BACKGROUND: Increasing direct-acting antiviral (DAA) treatment uptake is key to eliminating HCV infection as a public health threat in Canada. People living with human immunodeficiency virus (HIV) and hepatitis C (HCV) co-infection face barriers to HCV treatment initiation. We sought to identify interventions that could support HCV treatment initiation based on patient and HCV care provider perspectives. METHODS: Eleven people living with HIV with a history of HCV infection and 12 HCV care providers were recruited for this qualitative descriptive study. Participants created ranked-ordered lists of potential interventions during nominal groups (n = 4) and individual interviews (n = 6). Following the nominal group technique, transcripts and intervention lists underwent thematic analysis and ranking scores were merged to create consolidated and prioritized lists from patient and provider perspectives. RESULTS: Patient participants identified a total of eight interventions. The highest-ranked interventions were multidisciplinary clinics, HCV awareness campaigns and patient education, nurse- or pharmacist-led care, peer involvement, and more and better-prepared health professionals. Provider participants identified 11 interventions. The highest-ranked were mobile outreach, DAA initiation at pharmacies, a simplified process of DAA prescription, integration of primary and specialist care, and patient-centred approaches. CONCLUSION: Participants proposed alternatives to hospital-based specialist HCV care, which require increasing capacity for nurses, pharmacists, primary care providers, and peers to have more direct roles in HCV treatment provision. They also identified the need for structural changes and educational initiatives. In addition to optimizing HCV care, these interventions might result in broader benefits for the health of HIV-HCV co-infected people.

The FDA-Approved Drug Cobicistat Synergizes with Remdesivir To Inhibit SARS-CoV-2 Replication In Vitro and Decreases Viral Titers and Disease Progression in Syrian Hamsters.

Combinations of direct-acting antivirals are needed to minimize drug resistance mutations and stably suppress replication of RNA viruses. Currently, there are limited therapeutic options against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and testing of a number of drug regimens has led to conflicting results. Here, we show that cobicistat, which is an FDA-approved drug booster that blocks the activity of the drug-metabolizing proteins cytochrome P450-3As (CYP3As) and P-glycoprotein (P-gp), inhibits SARS-CoV-2 replication. Two independent cell-to-cell membrane fusion assays showed that the antiviral effect of cobicistat is exerted through inhibition of spike protein-mediated membrane fusion. In line with this, incubation with low-micromolar concentrations of cobicistat decreased viral replication in three different cell lines including cells of lung and gut origin. When cobicistat was used in combination with remdesivir, a synergistic effect on the inhibition of viral replication was observed in cell lines and in a primary human colon organoid. This was consistent with the effects of cobicistat on two of its known targets, CYP3A4 and P-gp, the silencing of which boosted the in vitro antiviral activity of remdesivir in a cobicistat-like manner. When administered in vivo to Syrian hamsters at a high dose, cobicistat decreased viral load and mitigated clinical progression. These data highlight cobicistat as a therapeutic candidate for treating SARS-CoV-2 infection and as a potential building block of combination therapies for COVID-19. IMPORTANCE The lack of effective antiviral treatments against SARS-CoV-2 is a significant limitation in the fight against the COVID-19 pandemic. Single-drug regimens have so far yielded limited results, indicating that combinations of antivirals might be required, as previously seen for other RNA viruses. Our work introduces the drug booster cobicistat, which is approved by the FDA and typically used to potentiate the effect of anti-HIV protease inhibitors, as a candidate inhibitor of SARS-CoV-2 replication. Beyond its direct activity as an antiviral, we show that cobicistat can enhance the effect of remdesivir, which was one of the first drugs proposed for treatment of SARS-CoV-2. Overall, the dual action of cobicistat as a direct antiviral and a drug booster can provide a new approach to design combination therapies and rescue the activity of compounds that are only partially effective in monotherapy.

Comprehensive review on molnupiravir in COVID-19: a novel promising antiviral to combat the pandemic.

Despite the progress in the management of COVID-19, effective oral antiviral agents are still lacking. In the present review, the potential beneficial effects of molnupiravir in the management of COVID-19 are discussed. A literature search in Google Scholar, Scopus, PubMed and clinicaltrials.gov for the relevant articles regarding the pharmacokinetics, pharmacodynamics and clinical trials of molnupiravir in the management of COVID-19 is conducted. Most of the preclinical studies and available clinical trials showed a favorable short-term safety profile of molnupiravir; however, given its possible genotoxic effects, further trials are required to confirm the long-term efficacy and safety of molnupiravir in patients with COVID-19.

The impact of COVID-19 on the cascade of care of HCV in the US and China.

BACKGROUND AND OBJECTIVES: The COVID-19 pandemic imperiled the global health system. We aimed to determine the impact of COVID-19 on the care continuum of HCV-infected patients. MATERIAL AND METHODS: Two hundred and fifty-six patients who were prescribed a course of DAA therapy at three tertiary medical centers in the US and China between January 1, 2019 to June 30, 2020 were included. We assessed the proportions of patients who completed DAA therapy and had HCV RNA testing during and after the end of therapy. We also assessed the impact of utilization of telemedicine. RESULTS: The proportion of patients undergoing HCV RNA testing during DAA treatment decreased from >81.7% before pandemic to 67.8% during the pandemic (P=0.006), with a more prominent decrease in the US. There were significant decreases in HCV RNA testing >12 (P<0.001) and >20 weeks (P<0.001) post-treatment during COVID-19 era. Compared to pre-COVID period, post-treatment clinic encounters during COVID-19 era decreased significantly in China (Xi'an: 13.6% to 7.4%; Nanjing: 16.7% to 12.5%) but increased in the US (12.5% to 16.7%), mainly due to the use of telemedicine. There was a 4-fold increase in utilization of telemedicine in the US. CONCLUSIONS: COVID-19 pandemic carried profound impact on care for HCV patients in both the US and China. HCV cure rate assessment decreased by half during COVID era but the proportion of patients finishing DAA therapy was not significantly affected. Increased utilization of telemedicine led to increased compliance with DAA therapy but did not encourage patients to have their laboratory assessment for HCV cure.

Development of a PROTAC-Based Targeting Strategy Provides a Mechanistically Unique Mode of Anti-Cytomegalovirus Activity.

Human cytomegalovirus (HCMV) is a major pathogenic herpesvirus that is prevalent worldwide and it is associated with a variety of clinical symptoms. Current antiviral therapy options do not fully satisfy the medical needs; thus, improved drug classes and drug-targeting strategies are required. In particular, host-directed antivirals, including pharmaceutical kinase inhibitors, might help improve the drug qualities. Here, we focused on utilizing PROteolysis TArgeting Chimeras (PROTACs), i.e., hetero-bifunctional molecules containing two elements, namely a target-binding molecule and a proteolysis-inducing element. Specifically, a PROTAC that was based on a cyclin-dependent kinase (CDK) inhibitor, i.e., CDK9-directed PROTAC THAL-SNS032, was analyzed and proved to possess strong anti-HCMV AD169-GFP activity, with values of EC50 of 0.030 µM and CC50 of 0.175 µM (SI of 5.8). Comparing the effect of THAL-SNS032 with its non-PROTAC counterpart SNS032, data indicated a 3.7-fold stronger anti-HCMV efficacy. This antiviral activity, as illustrated for further clinically relevant strains of human and murine CMVs, coincided with the mid-nanomolar concentration range necessary for a drug-induced degradation of the primary (CDK9) and secondary targets (CDK1, CDK2, CDK7). In addition, further antiviral activities were demonstrated, such as the inhibition of SARS-CoV-2 replication, whereas other investigated human viruses (i.e., varicella zoster virus, adenovirus type 2, and Zika virus) were found insensitive. Combined, the antiviral quality of this approach is seen in its (i) mechanistic uniqueness; (ii) future options of combinatorial drug treatment; (iii) potential broad-spectrum activity; and (iv) applicability in clinically relevant antiviral models. These novel data are discussed in light of the current achievements of anti-HCMV drug development.

Re-purposing of hepatitis C virus FDA approved direct acting antivirals as potential SARS-CoV-2 protease inhibitors.

A new coronavirus strain called as SARS-CoV-2 has emerged from Wuhan, China in late 2019 and it caused a worldwide pandemic in a few months. After the Second World War, it is the biggest calamity observed as there is no specific US Food and Drugs Administration (USFDA) approved drug or vaccine available globally for the treatment. Several clinical trials are ongoing for therapeutic alternatives, however with little success rate. Considering that the time is crucial, the drug repurposing and data obtained from in silico models are one of the most important approaches to identify possible lead inhibitors against SARS-CoV-2. More recently, the Direct Acting Antivirals (DAAs) are emerged as the most promising drugs to control viral infection. The Main Protease (Mpro), a key enzyme in the SARS-CoV-2 replication cycle, is found close homolog to the Hepatitis C Virus (HCV) protease and could be susceptible of blocking its activity by DAAs. In the current study, the DAAs were investigated as antivirals using structure based computational approach against Mpro of SARS-CoV-2 to propose them as new therapeutics. In total, 20 DAAs of HCV, including a reference compound O6K were docked against Mpro. The docked structures were examined and resulted in the identification of six highly promising DAAs i.e. beclabuvir, elbasvir, paritaprevir, grazoprevir, simeprevir, and asunapevir exhibiting high theoretical binding affinity to Mpro from SARS-CoV-2 in comparison to other DAAs. Furthermore, the post docking analysis revealed that Cys145, Glu166, His163, Thr26, His41, and Met165 played potential role for the binding of these DAAs inside binding site of Mpro. Furthermore, the correlation between binding energies were found in accord with the results from the reported IC50s for some DAAs. Overall, the current study provides insight to combat COVID-19 using FDA-approved DAAs as repurposed drugs.

COVID-19 Mid-term Impact on Hepatocellular Carcinoma in Patients With Hepatitis C Chronic Infection.

BACKGROUND/AIM: Liver injury has been frequently reported in association with SARS-CoV-2 infection, but data are still lacking regarding the impact of pre-existing liver damage and neoplasia on SARS-CoV-2 infection outcome and vice-versa. This study aimed to assess the effects of SARS-CoV-2 infection on hepatocellular carcinoma (HCC) in chronic hepatitis C virus (HCV) infected patients, both in therapeutic-naïve and patients treated with direct acting antivirals. PATIENTS AND METHODS: We conducted a retrospective cohort study on 21 patients with a personal history of HCV infection, that have been diagnosed with different forms of HCC and who were subsequently infected with SARS-CoV-2. Patients were monitored by liver function tests, tumoral markers, blood cell count, and coagulation profile periodically. RESULTS: Solitary HCC nodules were predominant among the subjects who achieved sustained virologic response, while multinodular and infiltrative patterns were mostly prevalent among the treatment-naïve group. Most patients had mild and moderate COVID-19 infections. CONCLUSION: Within the current global pandemic crisis, cancer patients are highly vulnerable and in need of constant monitoring. Among patients with HCC, the ones with cured HCV infection may be at a lower risk of fatality than those with active HCV infection, when diagnosed with SARS-CoV-2 infection.

The changing characteristics of patients infected with chronic hepatitis C virus from 2014 to 2019: Real-world data from the German Hepatitis C-Registry (DHC-R).

The number of patients diagnosed with hepatitis C virus (HCV) is markedly higher than the number initiating treatment indicating gaps in the care cascade, likely centred around reaching at-risk populations. Understanding changing characteristics of patients with HCV allows for targeted programs that increase linkage to care. We investigated changes in demographic and clinical characteristics of patients registered in the German Hepatitis C-Registry (DHC-R) from 1 January 2014 to 31 December 2019. The DHC-R is an ongoing, noninterventional, multicentre, prospective, observational cohort registry including 327 German centres. Patient characteristics were analysed over time in 7 phases for all patients completing a screening visit. Overall, 14,357 patients were enrolled. The percentage of treatment-naïve/non-cirrhotic patients increased from 34.4% in phase 1 (1 January-31 December 2014) to 68.2% in phase 7 (1 August-31 December 2019). The proportion of migrants, alcohol users, people who inject drugs, and those receiving opiate substitution therapy increased in later registry phases. Most patients (60.1%) were receiving comedication at baseline. The most prescribed comedications were drugs used to treat opioid dependence which increased from 9.2% in phase 1 to 24.0% in phase 7. The patients' mean age decreased from 52.3 years in phase 1 to 48.7 years in phase 7. From 2014 to 2019, the proportion of at-risk patients enrolling in the registry increased. To eliminate viral hepatitis as a major public health threat, a continued commitment to engaging underserved populations into the HCV care cascade is needed.

Reporter Replicons for Antiviral Drug Discovery against Positive Single-Stranded RNA Viruses.

Single-stranded positive RNA ((+) ssRNA) viruses include several important human pathogens. Some members are responsible for large outbreaks, such as Zika virus, West Nile virus, SARS-CoV, and SARS-CoV-2, while others are endemic, causing an enormous global health burden. Since vaccines or specific treatments are not available for most viral infections, the discovery of direct-acting antivirals (DAA) is an urgent need. Still, the low-throughput nature of and biosafety concerns related to traditional antiviral assays hinders the discovery of new inhibitors. With the advances of reverse genetics, reporter replicon systems have become an alternative tool for the screening of DAAs. Herein, we review decades of the use of (+) ssRNA viruses replicon systems for the discovery of antiviral agents. We summarize different strategies used to develop those systems, as well as highlight some of the most promising inhibitors identified by the method. Despite the genetic alterations introduced, reporter replicons have been shown to be reliable systems for screening and identification of viral replication inhibitors and, therefore, an important tool for the discovery of new DAAs.

High Cure Rates for Hepatitis C Virus Genotype 6 in Advanced Liver Fibrosis With 12 Weeks Sofosbuvir and Daclatasvir: The Vietnam SEARCH Study.

BACKGROUND: Genotype 6 is the most genetically diverse lineage of hepatitis C virus, and it predominates in Vietnam. It can be treated with sofosbuvir with daclatasvir (SOF/DCV), the least expensive treatment combination globally. In regional guidelines, longer treatment durations of SOF/DCV (24 weeks) are recommended for cirrhotic individuals, compared with other pangenotypic regimens (12 weeks), based on sparse data. Early on-treatment virological response may offer means of reducing length and cost of therapy in patients with liver fibrosis. METHODS: In this prospective trial in Vietnam, genotype 6-infected adults with advanced liver fibrosis or compensated cirrhosis were treated with SOF/DCV. Day 14 viral load was used to guide duration of therapy: participants with viral load <500 IU/mL at day 14 were treated with 12 weeks of SOF/DCV and those ≥500 IU/mL received 24 weeks. Primary endpoint was sustained virological response (SVR). RESULTS: Of 41 individuals with advanced fibrosis or compensated cirrhosis who commenced treatment, 51% had genotype 6a and 34% had 6e. The remainder had 6h, 6k, 6l, or 6o. One hundred percent had viral load <500 IU/mL by day 14, meaning that all received 12 weeks of SOF/DCV. One hundred percent achieved SVR12 despite a high frequency of putative NS5A inhibitor resistance-associated substitutions at baseline. CONCLUSIONS: Prescribing 12 weeks of SOF/DCV results in excellent cure rates in this population. These data support the removal of costly genotyping in countries where genotype 3 prevalence is <5%, in keeping with World Health Organization guidelines. NS5A resistance-associated mutations in isolation do not affect efficacy of SOF/DCV therapy. Wider evaluation of response-guided therapy is warranted.

Access to direct-acting antivirals for hepatitis C-negative transplant recipients receiving organs from hepatitis C-viremic donors.

PURPOSE: A barrier to using organs from hepatitis C virus (HCV)-viremic donors is the high cost of direct-acting antivirals (DAAs) and concerns about access for recipients after transplantation. The purpose of this study was to evaluate access, cost, and timing for HCV DAAs following transplantation. METHODS: This was a single-center, retrospective study of HCV-negative adult transplant recipients from June 2017 to December 2019 who received grafts from HCV-viremic and/or HCV-seropositive individuals and became HCV viremic after transplantation. RESULTS: Between June 2017 and December 2019, there were 60 HCV-negative transplant recipients who became viremic after receiving grafts from HCV-viremic or HCV-seropositive donors. Thirty-eight patients met the inclusion criteria (n = 25 with liver transplants, n = 6 with lung transplants, n = 4 with simultaneous liver and kidney transplants, and n = 3 with kidney transplants). Of these patients, 23 had commercial insurance, 13 had Medicare, and 2 had Medicaid. All patients ultimately received insurance coverage for treatment; however, 36 (95%) required prior authorization and 9 (24%) required appeals to obtain insurance coverage. The median time from DAA prescription to insurance approval was 6 days. The median time from transplantation to start of treatment was 29 days (range, 0-84 days). Patients with Medicaid insurance had a significantly longer time to insurance approval (31.5 vs 6 days, P = 0.007). The average out-of-pocket cost to patients was less than $10 a month after patient assistance. All patients who completed treatment and 12-week follow-up after treatment achieved a sustained virologic response (n = 36). CONCLUSION: In this study, all HCV-negative recipients who developed HCV following transplantation had access to DAA therapy, with the majority starting treatment in the first month after transplantation.

Crystal Structure of SARS-CoV-2 Main Protease in Complex with the Non-Covalent Inhibitor ML188.

Viral proteases are critical enzymes for the maturation of many human pathogenic viruses and thus are key targets for direct acting antivirals (DAAs). The current viral pandemic caused by SARS-CoV-2 is in dire need of DAAs. The Main protease (Mpro) is the focus of extensive structure-based drug design efforts which are mostly covalent inhibitors targeting the catalytic cysteine. ML188 is a non-covalent inhibitor designed to target SARS-CoV-1 Mpro, and provides an initial scaffold for the creation of effective pan-coronavirus inhibitors. In the current study, we found that ML188 inhibits SARS-CoV-2 Mpro at 2.5 µM, which is more potent than against SAR-CoV-1 Mpro. We determined the crystal structure of ML188 in complex with SARS-CoV-2 Mpro to 2.39 Å resolution. Sharing 96% sequence identity, structural comparison of the two complexes only shows subtle differences. Non-covalent protease inhibitors complement the design of covalent inhibitors against SARS-CoV-2 main protease and are critical initial steps in the design of DAAs to treat CoVID 19.

Current and Future Direct-Acting Antivirals Against COVID-19.

The coronavirus disease of 2019 (COVID-19) has caused an unprecedented global crisis. The etiological agent is a new virus called the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). As of October, 2020 there have been 45.4 million confirmed cases with a mortality rate of 2.6% globally. With the lack of a vaccine and effective treatments, the race is on to find a cure for the virus infection using specific antivirals. The viral RNA-dependent RNA polymerase, proteases, spike protein-host angiotensin-converting enzyme 2 binding and fusion have presented as attractive targets for pan-coronavirus and broad spectrum direct-acting antivirals (DAAs). This review presents a perspective on current re-purposing treatments and future DAAs.

Old Drugs for a New Virus: Repurposed Approaches for Combating COVID-19.

There is a large global unmet need for effective countermeasures to combat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19). The development of novel antiviral drugs is expensive and too slow to meet the immediate need. The repurposing of drugs that are approved or are under advanced clinical investigation provides a cost- and time-effective therapeutic solution. This review summarizes the major repurposed approaches that have been proposed or are already being studied in clinical trials for COVID-19. Among these approaches are drugs that aim to reduce SARS-CoV-2 replication by targeting either viral enzymatic functions or cellular factors required for the viral life cycle. Drugs that modulate the host immune response to SARS-CoV-2 infection by boosting it to enhance viral clearance or by suppressing it to prevent excessive inflammation and tissue injury represent another category. Lastly, we discuss means to discover repurposed drugs and the ongoing challenges associated with the off-label use of existing drugs in the context of the COVID-19 outbreak.