Is there still hope for the prophylactic hepatitis C vaccine? A review of different approaches.

Despite remarkable progress in the treatment of hepatitis C virus (HCV) infection, it remains a significant global health burden, necessitating the development of an effective prophylactic vaccine. This review paper presents the current landscape of HCV vaccine candidates and approaches, including more traditional, based on inactivated virus, and more modern, such as subunit protein, vectored, based on nucleic acids (DNA and mRNA) and virus-like particles. The concept of the HCV vaccine is first put in the context of viral genetic diversity and adaptive responses to HCV infection, an understanding of which is crucial in guiding the development of an effective vaccine against such a complex virus. Because ethical dimensions are also significant in vaccine research, development, and potential deployment, we also address them in this paper. The road to a safe and effective vaccine to prevent HCV infection remains bumpy due to the genetic variation of HCV and its ability to evade immune responses. The progress in cell-culture systems allowed for the production of an inactivated HCV vaccine candidate, which can induce cross-neutralizing antibodies in vitro, but whether this could prevent infection in humans is unknown. Subunit protein vaccine candidates that entered clinical trials elicited HCV-specific humoral and cellular responses, though it remains to be shown whether they translate into effective prevention of HCV infection or progression of infection to a chronic state. Such responses were also induced by a clinically tested vector-based vaccine candidate, which decreased the viral HCV load but did not prevent chronic HCV infection. These disappointments were not readily predicted from preclinical animal studies. The vaccine platforms employing virus-like particles, DNA, and mRNA provide opportunities for the HCV vaccine, but their potential in this context has yet to be shown. Ensuring the designed vaccine is based on conserved epitope(s) and elicits broadly neutralizing immune responses is also essential. Given failures in developing a prophylactic HCV vaccine, it is crucial to continue supporting national strategies, including funding for screening and treatment programs. However, these actions are likely insufficient to permanently control the HCV burden, encouraging further mobilization of significant resources for HCV vaccine research as a missing element in the elimination of viral hepatitis as a global public health.

New Insights into Bitopic Orthosteric/Allosteric Ligands of Cannabinoid Receptor Type 2.

Very recently, we have developed a new generation of ligands targeting the cannabinoid receptor type 2 (CB2R), namely JR compounds, which combine the pharmacophoric portion of the CB2R positive allosteric modulator (PAM), EC21a, with that of the CB2R selective orthosteric agonist LV62, both synthesized in our laboratories. The functional examination enabled us to identify JR14a, JR22a, and JR64a as the most promising compounds of the series. In the current study, we focused on the assessment of the bitopic (dualsteric) nature of these three compounds. Experiments in cAMP assays highlighted that only JR22a behaves as a CB2R bitopic (dualsteric) ligand. In parallel, computational studies helped us to clarify the binding mode of these three compounds at CB2R, confirming the bitopic (dualsteric) nature of JR22a. Finally, the potential of JR22a to prevent neuroinflammation was investigated on a human microglial cell inflammatory model.

Neighborhood poverty is associated with failure to be waitlisted and death during liver transplantation evaluation.

Liver transplantation (LT) is the final step in a complex care cascade. Little is known about how race, gender, rural versus urban residence, or neighborhood socioeconomic indicators impact a patient's likelihood of LT waitlisting or risk of death during LT evaluation. We performed a retrospective cohort study of adults referred for LT to the Indiana University Academic Medical Center from 2011 to 2018. Neighborhood socioeconomic status indicators were obtained by linking patients' addresses to their census tract defined in the 2017 American Community Survey. Descriptive statistics were used to describe completion of steps in the LT evaluation cascade. Multivariable analyses were performed to assess the factors associated with waitlisting and death during LT evaluation. There were 3454 patients referred for LT during the study period; 25.3% of those referred were waitlisted for LT. There was no difference seen in the proportion of patients from vulnerable populations who progressed to the steps of financial approval or evaluation start. There were differences in waitlisting by insurance type (22.6% of Medicaid vs. 34.3% of those who were privately insured; p < 0.01) and neighborhood poverty (quartile 1 29.6% vs. quartile 4 20.4%; p < 0.01). On multivariable analysis, neighborhood poverty was independently associated with waitlisting (odds ratio 0.56, 95% confidence interval [CI] 0.38-0.82) and death during LT evaluation (hazard ratio 1.49, 95% CI 1.09-2.09). Patients from high-poverty neighborhoods are at risk of failing to be waitlisted and death during LT evaluation.

Removal of medicaid restrictions were associated with increased hepatitis C virus treatment rates, but disparities persist.

Despite the release of a growing number of direct-acting antivirals and evolving policy landscape, many of those diagnosed with hepatitis C virus (HCV) have not received treatment. Those from vulnerable populations are at particular risk of being unable to access treatment, threatening World Health Organization (WHO) HCV elimination goals. The aim of this study was to understand the association between direct-acting antivirals approvals, HCV-related policy changes and access to HCV virus treatment in Indiana, and to explore access to treatment by race, birth cohort and insurance type. We performed a retrospective cohort study of adults with HCV from 05/2011-03/2021, using statewide electronic health data. Nine policy and treatment changes were defined a priori. A Lowess curve evaluated treatment trends over time. Monthly screening and treatment rates were examined. Multivariable logistic regression explored predictors of treatment. The population (N = 10,336) was 13.4% Black, 51.8% was born after 1965 and 44.7% was Medicaid recipients. Inflections in the Lowess curve defined four periods: (1) Interferon + DAA, (2) early direct-acting antivirals, (3) Medicaid expansion/optimization and (4) Medicaid restrictions (fibrosis/prescriber) removed. The largest increase in monthly treatment rates was during period 4, when Medicaid prescriber and fibrosis restrictions were removed (2.4 persons per month [PPM] in period 1 to 72.3 PPM in period 4, p < 0.001; 78.0% change in slope). Multivariable logistic regression analysis showed being born after 1965 (vs. before 1945; OR 0.69; 95% 0.49-0.98) and having Medicaid (vs. private insurance; OR 0.47; 95% CI 0.42-0.53), but not race was associated with lower odds of being treated. In conclusion, DAAs had limited impact on HCV treatment rates until Medicaid restrictions were removed. Additional policies may be needed to address HCV treatment-related age and insurance disparities.

The role of type I interferon in the treatment of COVID-19.

Although significant research has been done to find effective drugs against coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), no definite effective drug exists. Thus, research has now shifted towards immunomodulatory agents other than antivirals. In this review, we aim to describe the latest findings on the role of type I interferon (IFN)-mediated innate antiviral response against SARS-CoV-2 and discuss the use of IFNs as a medication for COVID-19. A growing body of evidence has indicated a promoting active but delayed IFNs response to SARS-CoV-2 and Middle East respiratory syndrome coronavirus in infected bronchial epithelial cells. Studies have demonstrated that IFNs' administration before the viral peak and the inflammatory phase of disease could offer a highly protective effect. However, IFNs' treatment during the inflammatory and severe stages of the disease causes immunopathology and long-lasting harm for patients. Therefore, it is critical to note the best time window for IFNs' administration. Further investigation of the clinical effectiveness of interferon for patients with mild to severe COVID-19 and its optimal timing and route of administration can be beneficial in finding a safe and effective antiviral therapy for the COVID-19 disease.

COVID-19 vaccinations: The unknowns, challenges, and hopes.

The entire world has been suffering from the coronavirus disease 2019 (COVID-19) pandemic since March 11, 2020. More than a year later, the COVID-19 vaccination brought hope to control this viral pandemic. Here, we review the unknowns of the COVID-19 vaccination, such as its longevity, asymptomatic spread, long-term side effects, and its efficacy on immunocompromised patients. In addition, we discuss challenges associated with the COVID-19 vaccination, such as the global access and distribution of vaccine doses, adherence to hygiene guidelines after vaccination, the emergence of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, and vaccine resistance. Despite all these challenges and the fact that the end of the COVID-19 pandemic is still unclear, vaccines have brought great hope for the world, with several reports indicating a significant decline in the risk of COVID19-related infection and hospitalizations.

Synthesis and In Vitro Characterization of Selective Cannabinoid CB2 Receptor Agonists: Biological Evaluation against Neuroblastoma Cancer Cells.

1,8-naphthyridine-3-carboxamide structures were previously identified as a promising scaffold from which to obtain CB2R agonists with anticancer and anti-inflammatory activity. This work describes the synthesis and functional characterization of new 1,8-naphthyridin-2(1H)-one-3-carboxamides with high affinity and selectivity for CB2R. The new compounds were able to pharmacologically modulate the cAMP response without modulating CB2R-dependent ß-arrestin2 recruitment. These structures were also evaluated for their anti-cancer activity against SH-SY5Y and SK-N-BE cells. They were able to reduce the cell viability of both neuroblastoma cancer cell lines with micromolar potency (IC50 of FG158a = 11.8 µM and FG160a = 13.2 µM in SH-SY5Y cells) by a CB2R-mediated mechanism. Finally, in SH-SY5Y cells one of the newly synthesized compounds, FG158a, was able to modulate ERK1/2 expression by a CB2R-mediated effect, thus suggesting that this signaling pathway might be involved in its potential anti-cancer effect.

Computational drug discovery and repurposing for the treatment of COVID-19: A systematic review.

BACKGROUND: Since the beginning of the novel coronavirus (SARS-CoV-2) disease outbreak, there has been an increasing interest in finding a potential therapeutic agent for the disease. Considering the matter of time, the computational methods of drug repurposing offer the best chance of selecting one drug from a list of approved drugs for the life-threatening condition of COVID-19. The present systematic review aims to provide an overview of studies that have used computational methods for drug repurposing in COVID-19. METHODS: We undertook a systematic search in five databases and included original articles in English that applied computational methods for drug repurposing in COVID-19. RESULTS: Twenty-one original articles utilizing computational drug methods for COVID-19 drug repurposing were included in the systematic review. Regarding the quality of eligible studies, high-quality items including the use of two or more approved drug databases, analysis of molecular dynamic simulation, multi-target assessment, the use of crystal structure for the generation of the target sequence, and the use of AutoDock Vina combined with other docking tools occurred in about 52%, 38%, 24%, 48%, and 19% of included studies. Studies included repurposed drugs mainly against non-structural proteins of SARS-CoV2: the main 3C-like protease (Lopinavir, Ritonavir, Indinavir, Atazanavir, Nelfinavir, and Clocortolone), RNA-dependent RNA polymerase (Remdesivir and Ribavirin), and the papain-like protease (Mycophenolic acid, Telaprevir, Boceprevir, Grazoprevir, Darunavir, Chloroquine, and Formoterol). The review revealed the best-documented multi-target drugs repurposed by computational methods for COVID-19 therapy as follows: antiviral drugs commonly used to treat AIDS/HIV (Atazanavir, Efavirenz, and Dolutegravir Ritonavir, Raltegravir, and Darunavir, Lopinavir, Saquinavir, Nelfinavir, and Indinavir), HCV (Grazoprevir, Lomibuvir, Asunaprevir, Ribavirin, and Simeprevir), HBV (Entecavir), HSV (Penciclovir), CMV (Ganciclovir), and Ebola (Remdesivir), anticoagulant drug (Dabigatran), and an antifungal drug (Itraconazole). CONCLUSIONS: The present systematic review provides a list of existing drugs that have the potential to influence SARS-CoV2 through different mechanisms of action. For the majority of these drugs, direct clinical evidence on their efficacy for the treatment of COVID-19 is lacking. Future clinical studies examining these drugs might come to conclude, which can be more useful to inhibit COVID-19 progression.

A Borderless Solution Is Needed for A Borderless Complexity, Like COVID-19, the Universal Invader.

This chapter briefly describes the universal intricacies caused by the COVID-19 pandemic, from the ineffectiveness of distance measures, the massive economic impacts, and the severe mental health challenges to the failure of finding a vaccine, a therapeutic agent or even accurately diagnosing the infection. The entire world is suffering, but every country is trying to combat this pandemic individually, and this deed is the main barrier that prevents reaching a peaceful end.

Introduction on Coronavirus Disease (COVID-19) Pandemic: The Global Challenge.

By driving the ongoing pandemic of coronavirus disease 2019 (COVID-19), coronaviruses have become a significant change in twenty-first-century medicine, healthcare systems, education, and the global economy. This chapter rapidly reviews the origin, immunopathogenesis, epidemiology, diagnosis, clinical manifestations, and potential therapeutics of COVID-19. It would also explore the effects of the introduction of a single virus, the so-called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), on the public health preparedness planning.

Biologic Therapy in Pediatric Chronic Rhinosinusitis: A Systematic Review.

OBJECTIVE: Provide clinicians with current evidence for biologic therapy in children with chronic rhinosinusitis with nasal polyposis (CRSwNP). DATA SOURCES: PubMed, MEDLINE, Cochrane, and clinical trial registries. REVIEW METHODS: Key search terms related to biologic therapy in pediatric CRSwNP were identified via a structured query of current medical literature and clinical trial databases. CONCLUSIONS: There is a dearth of active clinical trials and research studies for biologics targeting pediatric CRSwNP. There is an ongoing compassionate-use clinical trial involving Dupilumab for children with nasal polyps as well as only 1 published work specifically focused on Dupilumab for pediatric CRSwNP in the setting of aspirin-exacerbated respiratory disease. IMPLICATIONS FOR PRACTICE: For children with atopic dermatitis, asthma, and chronic idiopathic urticaria, biologic therapies such as Omalizumab, Dupilumab, and Mepolizumab have gained Food and Drug Administration approval. The role of biologic therapy in pediatric CRSwNP demonstrates significant promise in the comprehensive management of the unified airway. Additional Phase III trials are necessary to broaden clinical indications for children with comorbid conditions and complex sinonasal disease.

Antifungal and antibiofilm effects of probiotic Lactobacillus salivarius, zinc nanoparticles, and zinc nanocomposites against Candida albicans from Nile tilapia (Oreochromis niloticus), water and humans.

Introduction: Candida albicans (C. albicans) can form biofilms; a critical virulence factor that provides effective protection from commercial antifungals and contributes to public health issues. The development of new antifungal therapies, particularly those targeting biofilms, is imperative. Thus, this study was conducted to investigate the antifungal and antibiofilm effects of Lactobacillus salivarius (L. salivarius), zinc nanoparticles (ZnNPs) and nanocomposites (ZnNCs) on C. albicans isolates from Nile tilapia, fish wash water and human fish sellers in Sharkia Governorate, Egypt. Methods: A cross-sectional study collected 300 samples from tilapia, fish wash water, and fish sellers (100 each). Probiotic L. salivarius was immobilized with ZnNPs to synthesize ZnNCs. The study assessed the antifungal and antibiofilm activities of ZnNPs, L. salivarius, and ZnNCs compared to amphotericin (AMB). Results: Candida spp. were detected in 38 samples, which included C. albicans (42.1%), C. glabrata (26.3%), C. krusei (21.1%), and C. parapsilosis (10.5%). A total of 62.5% of the isolates were resistant to at least one antifungal agent, with the highest resistance to nystatin (62.5%). However, 75% of the isolates were highly susceptible to AMB. All C. albicans isolates exhibited biofilm-forming capabilities, with 4 (25%) isolates showing strong biofilm formation. At least one virulence-associated gene (RAS1, HWP1, ALS3, or SAP4) was identified among the C. albicans isolates. Probiotics L. salivarius, ZnNPs, and ZnNCs displayed antibiofilm and antifungal effects against C. albicans, with ZnNCs showing significantly higher inhibitory activity. ZnNCs, with a minimum inhibitory concentration (MIC) of 10 µg/mL, completely reduced C. albicans biofilm gene expression. Additionally, scanning electron microscopy images of C. albicans biofilms treated with ZnNCs revealed asymmetric, wrinkled surfaces, cell deformations, and reduced cell numbers. Conclusion: This study identified virulent, resistant C. albicans isolates with strong biofilm-forming abilities in tilapia, water, and humans, that pose significant risks to public health and food safety.

Trends in Racial and Ethnic Disparities in the Receipt of Lifesaving Procedures for Hospitalized Patients With Decompensated Cirrhosis in the US, 2009-2018.

Importance: Patients with decompensated cirrhosis are hospitalized for acute management with temporizing and lifesaving procedures. Published data to inform intervention development in this area are more than a decade old, and it is not clear whether there have been improvements in disparities in the receipt of these procedures over time. Objective: To evaluate the associations of race and ethnicity with receipt of procedures to treat decompensated cirrhosis over time in the US. Design, Setting, and Participants: This retrospective cross-sectional study analyzed National Inpatient Sample data on cirrhosis admissions among patients with portal hypertension-related complications from 2009 to 2018. All hospital discharges for individuals aged 18 years and older from 2009 to 2018 were assessed for inclusion. Admissions were included if they contained at least 1 cirrhosis-related International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) or International Statistical Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) code and at least 1 cirrhosis-related complication ICD-9-CM or ICD-10-CM code (ie, ascites, hepatic encephalopathy, variceal hemorrhage [VH], and hepatorenal syndrome [HRS]). Data were analyzed from January to June 2022. Exposure: Hospitalization for decompensated cirrhosis. Main Outcomes and Measures: The outcomes of interest were trends in the odds ratios (ORs) for receiving procedures (upper endoscopy, transjugular portosystemic shunt [TIPS], hemodialysis, and liver transplantation [LT]) for decompensated cirrhosis and mortality by race and ethnicity, modeled over time. Multivariable logistic regression was used to assess these outcomes. Results: Among 717 580 admissions (median [IQR] age, 58 [52-67] years), 345 644 patients (9.8%) were Black, 623 991 patients (17.6%) were Hispanic, and 2 340 031 patients (47.4%) were White. Based on the modeled trends, by 2018, there were no significant differences by race or ethnicity in the odds of receiving upper endoscopy for VH. However, Black patients remained less likely than White patients to undergo TIPS for VH (OR, 0.54; 95% CI, 0.47-0.62) and ascites (OR, 0.34; 95% CI, 0.31-0.38). The disparity in receipt of LT improved for Black and Hispanic patients over the study period; however, by 2018, both groups remained less likely to undergo LT than their White counterparts (Black: OR, 0.66; 95% CI, 0.61-0.70; Hispanic: OR, 0.74; 95% CI, 0.70-0.78). The odds of death in Black and Hispanic patients declined over the study period but remained higher in Black patients than White patients in 2018 (OR, 1.08; 95% CI, 1.05-1.11). Conclusions and Relevance: In this cross-sectional study of individuals hospitalized with decompensated cirrhosis, there were racial and ethnic disparities in receipt of complex lifesaving procedures and in mortality that persisted over time.

Exploring the application of immunotherapy against HIV infection in the setting of malignancy: A detailed review article.

According to the Joint United Nations Programme on HIV/AIDS (UNAIDS), as of 2019, approximately 42.2 million people have died from acquired immunodeficiency syndrome (AIDS)-related illnesses since the start of the epidemic. Antiretroviral therapy (ART) has significantly reduced mortality, morbidity, and incidence of the human immunodeficiency virus (HIV)/AIDS-defining cancers, taming once-dreaded disease into a benign chronic infection. Although the treatment has prolonged the patients' survival, general HIV prevalence has increased and this increase has dovetailed with an increasing incidence of Non-AIDS-defining cancers (NADCs) among people living with HIV (PLWH). This is happening when new promising approaches in both oncology and HIV infection are being developed. This review focuses on recent progress witnessed in immunotherapy approaches against HIV-related, Non-AIDS-defining cancers (NADCs), and HIV infection.

Longevity of immunity following COVID-19 vaccination: a comprehensive review of the currently approved vaccines.

It is unknown how long the immunity following COVID-19 vaccination lasts. The current systematic review provides a perspective on the persistence of various antibodies for available vaccines.Both the BNT162b2 and the mRNA-1273 induce the production of IgA antibodies, reflecting the possible prevention of the asymptomatic spread. The mRNA-1273 vaccine's antibodies were detectable until 6 months, followed by the AZD1222, 3 months, the Ad26.COV2.S and the BNT162b2 vaccines within 2 months.The BNT162b2 produced anti-spike IgGs 11 days after the first dose and peaked at day 21, whereas the AZD1222 induced a neutralizing effect 22 days after the first dose.These vaccines induce T-cell mediated immune responses too. Each one of the AZD1222, Ad26.COV2.S, mRNA-1273 mediates T-cell response immunity at days 14-22, 15, and 43 after the first dose, respectively. Whereas for the BNT162b1 and BNT162b2 vaccines, T-cell immunity is induced 7 days and 12 weeks after the booster dose, respectively.

Ventilatory performance of BASKA mask as an alternative to endotracheal intubation in short-term gynecologic laparoscopic procedures: a prospective randomized clinical trial.

BACKGROUND: Using laryngeal mask airways (LMAs) in laparoscopic surgery is still controversial because of the risk of insufficient ventilation and gastric overinflation. We investigated the use of BASKA LMA as an alternative to endotracheal intubation in low-risk females undergoing short-term gynecologic laparoscopic surgeries in Trendelenburg position under general anesthesia and positive pressure ventilation. METHODS: Sixty-five females (19-43 years), ASA (I-II) were scheduled to receive endotracheal tube (ETT group, N.=32) or BASKA mask (BASKA group, N.=33) for airway management. Assessments included insertion time and score, intraoperative lung mechanics, oropharyngeal leak pressure (OLP), ventilatory score, leak fraction, perioperative lung spirometry, and adverse effects. Timepoints were after device insertion, pneumoperitoneum inflation, Trendelenburg position, at 15, 30, 45 minutes intraoperatively and at end of surgery. RESULTS: The median insertion time was shorter in BASKA group (21.0 [18-38] s), compared with ETT group (27.0 [24-33] s, P=0.000). First-time success rate for insertion of BASKA mask was 87.9% (29 patients). The peak inflation pressure, calculated dynamic compliance, ventilatory score and lung spirometry data showed no significant difference between the two groups. The median leak fraction was higher in BASKA group after insertion (P=0.012) and after Trendelenburg position (P=0.032), with no significant differences afterwards. The median OLP after insertion was 32.0 (29-35) cmH2O which decreased after pneumoperitoneum inflation (31.0 [27-33] cmH2O, P=0.000), and after Trendelenburg position (30.0 [27-32] cmH2O, P=0.000) and remained stable at this range. CONCLUSIONS: BASKA mask can be considered as a safe alternative to ETT with comparable ventilatory performance in low-risk females undergoing short-term gynecologic laparoscopic surgeries.

Design, synthesis and biological evaluation of novel orthosteric-allosteric ligands of the cannabinoid receptor type 2 (CB2R).

It is well known that G protein-coupled receptors (GPCRs) assume multiple active states. Orthosteric ligands and/or allosteric modulators can preferentially stabilize specific conformations, giving rise to pathway-biased signaling. One of the most promising strategies to expand the repertoire of signaling-selective GPCR activators consists of dualsteric agents, which are hybrid compounds consisting of orthosteric and allosteric pharmacophoric units. This approach proved to be very promising showing several advantages over monovalent targeting strategies, including an increased affinity or selectivity, a bias in signaling pathway activation, reduced off-target activity and therapeutic resistance. Our study focused on the cannabinoid receptor type 2 (CB2R), considered a clinically promising target for the control of brain damage in neurodegenerative disorders. Indeed, CB2R was found highly expressed in microglial cells, astrocytes, and even in some neuron subpopulations. Here, we describe the design, synthesis, and biological evaluation of two new classes of potential dualsteric (bitopic) CB2R ligands. The new compounds were obtained by connecting, through different linkers, the pharmacophoric portion of the CB2R positive allosteric modulator (PAM), EC21a, with that of the CB2R selective orthosteric agonist LV62, both developed in our laboratories. A preliminary screening enabled us to identify compound JR64a as the most promising of the series. Indeed, functional examination highlighted a signaling 'bias' in favor of G protein activation over ßarrestin2 recruitment, combined with high affinity for CB2R and the ability to efficiently prevent inflammation in human microglial cells (HMC3) exposed to LPS/TNFα stimulation, thus demonstrating great promise for the treatment of neurodegenerative diseases.

Novel Potent and Selective Agonists of the GPR55 Receptor Based on the 3-Benzylquinolin-2(1H)-One Scaffold.

A growing body of evidence underlines the crucial role of GPR55 in physiological and pathological conditions. In fact, GPR55 has recently emerged as a therapeutic target for several diseases, including cancer and neurodegenerative and metabolic disorders. Several lines of evidence highlight GPR55's involvement in the regulation of microglia-mediated neuroinflammation, although the exact molecular mechanism has not been yet elucidated. Nevertheless, there are only a limited number of selective GPR55 ligands reported in the literature. In this work, we designed and synthesized a series of novel GPR55 ligands based on the 3-benzylquinolin-2(1H)-one scaffold, some of which showed excellent binding properties (with Ki values in the low nanomolar range) and almost complete selectivity over cannabinoid receptors. The full agonist profile of all the new derivatives was assessed using the p-ERK activation assay and a computational study was conducted to predict the key interactions with the binding site of the receptor. Our data outline a preliminary structure-activity relationship (SAR) for this class of molecules at GPR55. Some of our compounds are among the most potent GPR55 agonists developed to date and could be useful as tools to validate this receptor as a therapeutic target.

Oral antiviral treatments for COVID-19: opportunities and challenges.

The use of antiviral COVID-19 medications can successfully inhibit SARS-CoV-2 replication and prevent disease progression to a more severe form. However, the timing of antiviral treatment plays a crucial role in this regard. Oral antiviral drugs provide an opportunity to manage SARS-CoV-2 infection without a need for hospital admission, easing the general burden that COVID-19 can have on the healthcare system. This review paper (i) presents the potential pharmaceutical antiviral targets, including various host-based targets and viral-based targets, (ii) characterizes the first-generation anti-SARS-CoV-2 oral drugs (nirmatrelvir/ritonavir and molnupiravir), (iii) summarizes the clinical progress of other oral antivirals for use in COVID-19, (iv) discusses ethical issues in such clinical trials and (v) presents challenges associated with the use of oral antivirals in clinical practice. Oral COVID-19 antivirals represent a part of the strategy to adapt to long-term co-existence with SARS-CoV-2 in a manner that prevents healthcare from being overwhelmed. It is pivotal to ensure equal and fair global access to the currently available oral antivirals and those authorized in the future.