Apovir (pleconaril/ribavirin) / Apodemus - LARVOL DELTA

Novel Synergistic Anti-Enteroviral Drug Combinations. (PubMed, Viruses) - " We confirmed anti-enteroviral activities of pleconaril, rupintrivir, cycloheximide, vemurafenib, remdesivir, emetine, and anisomycin and identified novel synergistic rupintrivir-vemurafenib, vemurafenib-pleconaril and rupintrivir-pleconaril combinations against EV1 infection. Because rupintrivir, vemurafenib, and pleconaril require lower concentrations to inhibit enterovirus replication in vitro when combined, their cocktails may have fewer side effects in vivo and, therefore, should be further explored in preclinical and clinical trials against EV1 and other enterovirus infections."

Journal • Infectious Disease • Oncology

A patent review on pharmaceutical and therapeutic applications of oxadiazole derivatives for the treatment of chronic diseases (2013-2021). (PubMed, Expert Opin Ther Pat) - "The rapid development in the field of oxadiazole-containing structures is confirmed by the development of numerous clinical drugs such as doxazosin, nesapidil, pleconaril, fasiplon, ataluren, zibotentan, and prenoxdiazine as selected examples. For instance, the oxadiazole-based compounds have shown the ability to modulate a variety of receptors including the M4 receptor agonists, S1P1 receptor modulators, SSTR5 antagonists, orexin type-2 receptor agonists, liver X receptor agonists, and many more. This testifies to the special features associated with the oxadiazole scaffold making it a significant pharmacophore."

Journal • Review • Oncology • SSTR5

Structure of Human Enterovirus 70 and Its Inhibition by Capsid-Binding Compounds. (PubMed, J Virol) - "Nevertheless, we show that the pocket can be targeted by the antiviral compounds WIN51711 and pleconaril, which block virus infection...Furthermore, we elucidated the structures of EV70 in complex with two inhibitors that block virus infection, and we describe the mechanism of their binding to the virus capsid. These results enable the development of therapeutics against EV70."

Journal • Conjunctivitis • Hematological Disorders • Infectious Disease • Ocular Infections • Ocular Inflammation • Ophthalmology

Application of a VP4/VP2-inferred transmission clusters in estimating the impact of interventions on rhinovirus transmission. (PubMed, Virol J) - "Here, we presented a network-based approach of which the degree of RV spread that fuel disease transmission in the region was mapped for the first time. The utilization of RV transmission clusters in assessing the putative impact of interventions on disease transmission at the population level was demonstrated."

Journal • Infectious Disease • Respiratory Diseases

Effects of double combinations of enterovirus replication inhibitors against Coxsackie B viruses. (PubMed, Acta Virol) - "Compounds with different mechanisms of action were studied: pleconaril, guanidine.HCl, MDL-860 and oxoglaucine...No increased cytotoxicity was manifested in any of the tested double combinations. Keywords: antivirals; combination activity; Coxsackieviruses."

Journal

Potential Virus Involvement in Alzheimer's Disease: Results from a Phase IIa Trial Evaluating Apovir, an Antiviral Drug Combination. (PubMed, J Alzheimers Dis Rep) - "The trial evaluated whether Apovir, a combination of two antiviral agents, pleconaril (active on enteroviruses) and ribavirin (active on several viruses), could slow AD progression. New trials are needed to verify if the indications of effect observed can be confirmed and which component(s) in Apovir contributed to such effects. Pleconaril alone may be studied to improve the tolerability and to verify if enterovirus is involved in the disease process."

Clinical • Journal • P2a data • Alzheimer's Disease • CNS Disorders • Infectious Disease

[VIRTUAL] Effect of Double Combinations Against Coxsackievirus B3 and Poliovirus (WMF 2021) - "An additive effect was exhibited when pocapavir was combined with 2-(alpha-hydroxybenzyl)-benzimidazole (HBB) and pleconaril against PV-1. Tested combinations had no cytotoxicity effect on uninfected HEp-2 cells."

Cardiovascular • CNS Disorders • Gastrointestinal Disorder • Hepatology • Infectious Disease • Inflammation • Pancreatitis • Respiratory Diseases • Septic Shock

[VIRTUAL] Triple Combinations Applied via Consecutive Alternating Administration in Mice Infected with Coxsackievirus B3 (WMF 2021) - "In comparison with placebo groups the monotherapeutic course with pleconaril demonstrated some independent antiviral effect. It was found that pocapavir, vapendavir, MDL-860 and oxoglaucine monotherapies were without a protective effect."

Preclinical • Infectious Disease

Sub-structure-based screening and molecular docking studies of potential enteroviruses inhibitors. (PubMed, Comput Biol Chem) - "Pleconaril, a broad spectrum anti-rhinoviral compound, has been used as a drug of choice for URTIs for over a decade...Molecular docking studies were then used to study their binding interaction at the molecular level. Interestingly, we have identified 3 residues that is worth further investigation in upcoming molecular dynamics simulation systems of their contribution in stable interaction."

Journal • Infectious Disease • Respiratory Diseases

Consecutive alternating administration as an effective anti-coxsackievirus B3 in vivo treatment scheme. (PubMed, Arch Virol) - "Applying the CAA approach with a combination of pleconaril (capsid binder), guanidine HCl (viral 2C inhibitor), and oxoglaucine (PI4KB inhibitor) (PGO) was found to be effective in the treatment of newborn mice infected with a massive inoculum (20 MLD) of the coxsackievirus B3 cardiotropic Woodruff or neurotropic Nancy strain. In addition to preventing drug resistance, the CAA approach resulted in the parallel development of increased susceptibility to the compounds in the PGO combination. These observations demonstrate the therapeutic potential of the CAA approach for treatment of enterovirus infections."

Journal • Preclinical • Infectious Disease

Clinical characteristics of severe neonatal enterovirus infection: a systematic review. (PubMed, BMC Pediatr) - "Lethality was high in neonates with severe enterovirus infection, especially in those complicated with myocarditis. The most common symptoms included temperature abnormalities, rash, and poor feeding. The chief supportive treatment consisted of transfusion of blood components, mechanical ventilation, and ECMO. Empirical antibiotics and IVIG were widely used. Antiviral medications included pocapavir and pleconaril; however, more clinical evidence regarding their efficacy is needed."

Clinical • Journal • Review • Cardiovascular • CNS Disorders • Hematological Disorders • Hepatology • Infectious Disease

Novel pleconaril derivatives: Influence of substituents in the isoxazole and phenyl rings on the antiviral activity against enteroviruses. (PubMed, Eur J Med Chem) - "Compound 10g demonstrated markedly less CYP3A4 induction than pleconaril, was non-mutagenic, and was bioavailable after intragastric administration in mice. These results highlight compound 10g as a promising potential candidate as a broad spectrum enterovirus and rhinovirus inhibitor for further preclinical investigations."

Journal • Infectious Disease

Effect of consecutive alternating administration of a triple combination of anti-enteroviral compounds in mice infected with coxsackievirus B3. (PubMed, Pathog Dis) - "It was established that in infection with cardiotropic Woodruff strain the combination of pleconaril, МDL-860 and oxoglaucine (PMO) subjected to the CAA scheme, a significant protective effect was observed...Toxicity of PMO applied via the CAA scheme and in the monotherapeutic courses in both healthy and CVB3 infected animals was recorded. All data obtained prove the potential of the CAA treatment scheme for development of effective chemotherapy of enterovirus infections."

Journal • Preclinical • Infectious Disease

Automated cell-based luminescence assay for profiling antiviral compound activity against enteroviruses. (PubMed, Sci Rep) - "Antiviral efficacy was determined by measuring the ATP levels in cells that were protected from the viral cytopathic effect (CPE) by the antiviral compounds pleconaril and rupintrivir...The assay exhibited excellent robustness, with Z'-factor values between 0.75 and 0.82, coefficients of variation between 0.33% and 1.45%, and signal-to-background ratios ranging from 6.92 to 22.6 when testing three enterovirus A71 isolates circulating in China. The assay was also suitable for screening other picornaviruses, such as poliovirus, coxsackievirus, echovirus, and parechovirus."

Journal • Preclinical • Infectious Disease

Midazolam Limited Sampling Strategy With a Population Pharmacokinetic Approach to Simultaneously Estimate Cytochrome P450 (CYP) 3A Constitutive, Inhibition, and Induction/Activation Conditions in Healthy Adults. (PubMed, J Clin Pharmacol) - "Ketoconazole, rifampin, and pleconaril were significant covariates of CL, while ketoconazole, rifampin, and grapefruit juice were significant covariates for F. Typical midazolam CL and F estimates were 32.9 L/h and 0.31 for the constituent state, while the ratio of inducer/inhibitor for midazolam CL and CL/F for the induced/inhibited (rifampin/ketoconazole) states were 14.2 and 85.3. Exclusively during CYP3A inhibitory conditions, the 4- and 6-hour limited sampling model had acceptable limits of r , bias, and precision. Consequently, development of a single- or 2-time point midazolam limited sampling model for general, widespread use to simultaneously evaluate various CYP3A conditions remains elusive."

Clinical • Journal • PK/PD data

[VIRTUAL] Precision-cut lung slices as an in vitro model for testing of novel therapeutic agents (ERS 2020) - "In inflammation model, dexamethasone inhibited LPS induced TNFα and IL-6 production in dose dependent manner. In RV1B infected PCLS, increased viral load and IFNλ production, were reduced by rupintrivir and pleconaril, while rupintrivir also diminished production of CCL5...Conclusions We have successfully established in vitro models of pulmonary fibrosis, inflammation and viral lung infection in PCLS, and validated them with reference compounds. We have also shown that PCLS are suitable for assessing compounds' lung toxicity."

Preclinical • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Infectious Disease • Respiratory Diseases • CASP3 • CCL5 • IL6 • TNFA

Viral structural proteins as targets for antivirals. (PubMed, Curr Opin Virol) - "In rhinovirus and poliovirus, compounds like pleconaril bind capsid and block RNA release...Despite the biological diversity between viruses and the chemical diversity between antiviral molecules, we observe common features in these antivirals' mechanisms of action. These approaches work by stabilizing protein-protein interactions."

Journal • Review • Hepatitis B • Infectious Disease

Effectiveness of Antivirals in a Type 1 Diabetes Model and the Move Toward Human Trials. (PubMed, Viral Immunol) - "In the present study we show significant clinical response in DP-BB rats using antiviral compounds available for human use (Pleconaril, Efavirenz, and Ribavirin). Based on these data it would be of interest to test antiviral treatment in patients with newly diagnosed T1D. Successful outcome will offer both proof of concept regarding the role of virus involvement in the disease and possibly a first generation treatment interrupting a persistent infection and stopping β-cell destruction."

Journal • Diabetes • Metabolic Disorders • Type 1 Diabetes Mellitus

nanoDSF: In vitro Label-Free Method to Monitor Picornavirus Uncoating and Test Compounds Affecting Particle Stability. (PubMed, Front Microbiol) - "Importantly, nanoDSF correctly identified the thermal stabilization of RV-A2 by pleconaril, a prototypic pocket-binding antiviral compound. NanoDFS is thus a label-free, high throughput-customizable, attractive alternative for the discovery of capsid-binding compounds impacting on viral stability."

Journal • Preclinical

A Novel Capsid Binding Inhibitor Displays Potent Antiviral Activity against Enterovirus D68. (PubMed, ACS Infect Dis) - "However, a recombination virus encoding VP1-A129V appeared to have compromised fitness of replication compared to the wild-type EV-D68 virus as shown by the competition growth assay. Overall, the hit compound identified in this study, R856932, represents a promising starting point with a confirmed mechanism of action that can be further developed into EV-D68 antivirals."

Journal

Characterization of a new anti-enterovirus 68 compound purified from avocado. (PubMed, ACS Infect Dis) - "Resistant mutations of EV-D68 (VP3-V24I, S173P, and S180G) to avoenin confer cross resistance to pleconaril, an uncoating inhibitor of EV-D68. The inhibitory effect of avoenin is substantially specific to EV-D68 among the EVs. This work reveals avoenin as the identity of anti-EV-D68 activity in avocado, and offers insights into development of novel and effective strategy to overcome EV-D68 infection and its related respiratory diseases."

Journal • Respiratory Diseases

Eradication of persistent coxsackievirus B infection from a pancreatic cell line with clinically used antiviral drugs. (PubMed, J Clin Virol) - "The identified drugs are feasible candidates for clinical trials among patients with persistent coxsackievirus B infections or chronic enterovirus-associated diseases."

Journal • Cardiovascular • Diabetes • Fatigue • Immunology • Infectious Disease • Metabolic Disorders • Type 1 Diabetes Mellitus

Antiviral activity of broad-spectrum and enterovirus-specific inhibitors against clinical isolates of enterovirus D68. (PubMed) - "Resistance to pleconaril maps to V69A in VP1 and resistance to rupintrivir to V104I in the 3C protease. A structural explanation is provided why both mutations may cause resistance."

Journal • Biosimilar

Cutaneous manifestations of systemic viral diseases in neonates: an update. (PubMed) - Curr Opin Pediatr - "Neonatal rashes may be harmless and transient, whereas others may reflect the presence of a severe systemic illness. Recognizing key cutaneous features of viral-associated rashes may aid in the prompt and accurate diagnosis and treatment of neonatal viral illnesses."

Journal • Biosimilar • Immunology • Ophthalmology

Detection of Enteric Viruses in Fecal Specimens from Nonbacterial Foodborne Gastroenteritis Outbreaks in Tokyo, Japan between 1966 and 1983. (PubMed) - Jpn J Infect Dis - "A phylogenetic analysis using the complete VP1 region and the P2 domain demonstrated that NoV GII.4 strains collected between 1975 and 1980 were clustered together with archival strains collected in mid-1970s in the USA. In contrast, a NoV GII.4 strain collected in 1983 formed a branch independent from reference strains detected in mid-1970s to 2012."

Journal • Biosimilar • Gene Therapies • Immunology