Resistance profiles for the investigational neuraminidase inhibitor AV5080 in influenza A and B viruses.

Neuraminidase inhibitors (NAIs) are recommended for influenza treatment and prevention worldwide. The most widely prescribed NAI is oral oseltamivir, while inhaled zanamivir is less commonly used. Using phenotypic neuraminidase (NA) enzymatic assays and molecular modeling approaches, we examined the ability of the investigational orally-dosed NAI AV5080 to inhibit viruses of the influenza A(H1N1)pdm09, A(H3N2), A(H5N1), and A(H7N9) subtypes and the influenza B/Victoria- and B/Yamagata-lineages containing NA substitutions conferring oseltamivir or zanamivir resistance including: NA-R292K, NA-E119G/V, NA-H274Y, NA-I122L/N, and NA-R150K.

The Efficacy of Aprotinin Combinations with Selected Antiviral Drugs in Mouse Models of Influenza Pneumonia and Coronavirus Infection Caused by SARS-CoV-2.

The efficacy of aprotinin combinations with selected antiviral-drugs treatment of influenza virus and coronavirus (SARS-CoV-2) infection was studied in mice models of influenza pneumonia and COVID-19. The high efficacy of the combinations in reducing virus titer in lungs and body weight loss and in increasing the survival rate were demonstrated. This preclinical study can be considered a confirmatory step before introducing the combinations into clinical assessment.

Safety and efficacy of aviandr in patients with generalized anxiety disorder: A multicenter, randomized, double-blind, placebo-controlled, dose-finding, pilot study.

Generalized anxiety disorder (GAD) is associated with an imbalance in the functioning of the stimulating neurotransmitter systems in human's brain. We studied the safety and therapeutic efficacy of aviandr, the new noradrenergic and specific serotonergic antidepressant, for GAD patients in the phase II, double-blind, placebo-controlled, randomized, multicenter, pilot trial at 17 clinical sites of the Russian Federation. 129 eligible patients were 18 years and older and met the criteria for GAD diagnosis.

Effect of Aprotinin and Avifavir Combination Therapy for Moderate COVID-19 Patients.

COVID-19 is a contagious multisystem inflammatory disease caused by a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We studied the efficacy of Aprotinin (nonspecific serine proteases inhibitor) in combination with Avifavir or Hydroxychloroquine (HCQ) drugs, which are recommended by the Russian Ministry of Health for the treatment therapy of moderate COVID-19 patients. This prospective single-center study included participants with moderate COVID-19-related pneumonia, laboratory-confirmed SARS-CoV-2, and admitted to the hospitals.

Synthesis, inhibitory activity and oral dosing formulation of AV5124, the structural analogue of influenza virus endonuclease inhibitor baloxavir.

Background: The development and clinical implementation of the cap-dependent endonuclease (CEN) inhibitor baloxavir marboxil was a breakthrough in influenza therapy, but it was associated with the emergence of drug-resistant variants.

Objectives: To design and synthesize structural analogues of CEN inhibitors and evaluate their safety, pharmacokinetics and antiviral potency in vitro and in vivo.

Methods: The drug candidate AV5124 and its active metabolite AV5116 were synthesized based on pharmacophore modelling.

Synthesis, biological evaluation and in silico modeling of novel pan-genotypic NS5A inhibitors.

A series of novel small-molecule pan-genotypic hepatitis C virus (HCV) NS5A inhibitors with picomolar activity containing 2-[(2S)-pyrrolidin-2-yl]-5-[4-(4-{2-[(2S)-pyrrolidin-2-yl]-1H-imidazol-5-yl}buta-1,3-diyn-1-yl)phenyl]-1H-imidazole core was designed based on molecular modeling study and SAR analysis. The constructed in silico model and docking study provide a deep insight into the binding mode of this type of NS5A inhibitors. Based on the predicted binding interface we have prioritized the most crucial diversity points responsible for improving antiviral activity.

Non-rigid Diarylmethyl Analogs of Baloxavir as Cap-Dependent Endonuclease Inhibitors of Influenza Viruses.

4-Substituted 2,4-dioxobutanoic acids inhibit influenza virus cap-dependent endonuclease (CEN) activity. Baloxavir marboxil, , is approved for treating influenza virus infections. We describe here the synthesis and biological evaluation of active compounds, -, and their precursors (, , , and ) with flexible bulky hydrophobic groups instead of the rigid polyheterocyclic moieties.

AVIFAVIR for Treatment of Patients With Moderate Coronavirus Disease 2019 (COVID-19): Interim Results of a Phase II/III Multicenter Randomized Clinical Trial.

In May 2020 the Russian Ministry of Health granted fast-track marketing authorization to RNA polymerase inhibitor AVIFAVIR (favipiravir) for the treatment of COVID-19 patients. In the pilot stage of Phase II/III clinical trial, AVIFAVIR enabled SARS-CoV-2 viral clearance in 62.5% of patients within 4 days, and was safe and well-tolerated.

Synthesis, biological evaluation and in silico modeling of novel integrase strand transfer inhibitors (INSTIs).

Although a relatively wide range of therapeutic options is currently available for the treatment of HIV/AIDS, it is still among the most serious and virulent diseases and is associated with a high mortality rate. Integrase strand transfer inhibitors (INSTIs), e.g.

Chemistry and Hypoglycemic Activity of GPR119 Agonist ZB-16.

This article is to highlight the chemical properties and primary pharmacology of novel GPR119 agonist ZB-16 and its analogs, which were rejected during the screening. Experiments were performed (specific activity, metabolism and cell toxicity) and (hypoglycemic activity and pharmacokinetics). ZB-16 exhibits nanomolar activity (EC50 = 7.

Novel water-soluble lignin derivative BP-Cx-1: identification of components and screening of potential targets and .

Identification of molecular targets and mechanism of action is always a challenge, in particular - for natural compounds due to inherent chemical complexity. BP-Cx-1 is a water-soluble modification of hydrolyzed lignin used as the platform for a portfolio of innovative pharmacological products aimed for therapy and supportive care of oncological patients. The present study describes a new approach, which combines screening of potential molecular targets for BP-Cx-1 using Diversity Profile - P9 panel by Eurofins Cerep (France) with a search of possible active components in ChEMBL - manually curated chemical database of bioactive molecules with drug-like properties.

Design, synthesis and biological evaluation of novel 5-oxo-2-thioxoimidazolidine derivatives as potent androgen receptor antagonists.

A series of novel highly active androgen receptor (AR) antagonists containing spiro-4-(5-oxo-3-phenyl-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile core was designed based on the SAR studies available from the reported AR antagonists and in silico modeling. Within the series, compound (R)-6 (ONC1-13B) and its related analogues, including its active N-dealkylated metabolite, were found to be the most potent molecules with the target activity (IC50, androgen-sensitive human PCa LNCaP cells) in the range of 59-80 nM (inhibition of PSA production). The disclosed hits were at least two times more active than bicalutamide, nilutamide and enzalutamide within the performed assay.

Discovery of novel highly potent hepatitis C virus NS5A inhibitor (AV4025).

A series of next in class small-molecule hepatitis C virus (HCV) NS5A inhibitors with picomolar potency containing 2-pyrrolidin-2-yl-5-{4-[4-(2-pyrrolidin-2-yl-1H-imidazol-5-yl)buta-1,3-diynyl]phenyl}-1H-imidazole cores was designed based on the SAR studies available for the reported NS5A inhibitors. Compound 13a (AV4025), with (S,S,S,S)-stereochemistry (EC50 = 3.4 ± 0.

Novel oral anti-influenza drug candidate AV5080.

Objectives: Development of a novel drug candidate with improved potency against influenza virus neuraminidase compared with currently available therapeutics, and high activity against oseltamivir-resistant viruses.

Methods: A number of synthetic compounds were evaluated for antiviral properties in vitro and in vivo. Three-dimensional molecular docking, assisted by a pharmacophore model, was applied to classify compounds within the series by their inhibitory potency.

Preclinical Development of ONC1-13B, Novel Antiandrogen for Prostate Cancer Treatment.

Recently new drugs targeting androgen-dependent axis have been approved for the treatment of castration-resistant prostate cancer (CRPC) - Zytiga and Xtandi (formerly MDV3100), several other candidates (for example, ARN-509) are in early phases of clinical trials. However despite significant improvement in overall survival with new treatments it is evident that resistance to these drugs develops. One of the approaches to overcome it is combination therapy and from this point of view some potential for drug-drug interactions can limit the application of the drug.

Novel oral anti-influenza prodrug candidate AV5075S.

Objectives: Development of a novel drug candidate with improved activity against influenza virus neuraminidase (NA) compared with currently available therapeutics.

Methods: Synthesized compounds were evaluated in vitro and in vivo. Three-dimensional molecular docking was successfully applied to classify compounds within the series by inhibitory potency.

Novel aryl and heteroaryl substituted N-[3-(4-phenylpiperazin-1-yl)propyl]-1,2,4-oxadiazole-5-carboxamides as selective GSK-3 inhibitors.

Synthesis, biological evaluation, and SAR dependencies for a series of novel aryl and heteroaryl substituted N-[3-(4-phenylpiperazin-1-yl)propyl]-1,2,4-oxadiazole-5-carboxamide inhibitors of GSK-3beta kinase are described. The inhibitory activity of the synthesized compounds is highly dependent on the character of substituents in the phenyl ring and the nature of terminal heterocyclic fragment of the core molecular scaffold. The most potent compounds from this series contain 3,4-di-methyl or 2-methoxy substituents within the phenyl ring and 3-pyridine fragment connected to the 1,2,4-oxadiazole heterocycle.

Nuclear oncoprotein prothymosin alpha is a partner of Keap1: implications for expression of oxidative stress-protecting genes.

Animal cells counteract oxidative stress and electrophilic attack through coordinated expression of a set of detoxifying and antioxidant enzyme genes mediated by transcription factor Nrf2. In unstressed cells, Nrf2 appears to be sequestered in the cytoplasm via association with an inhibitor protein, Keap1. Here, by using the yeast two-hybrid screen, human Keap1 has been identified as a partner of the nuclear protein prothymosin alpha.

Sensing prothymosin alpha origin, mutations and conformation with monoclonal antibodies.

To overcome poor immunogenicity of prothymosin alpha, a small and highly acidic nuclear protein involved in cell proliferation, production of anti-prothymosin alpha antibodies in mice immunized with free human prothymosin alpha, with prothymosin alpha coupled to different carriers and with prothymosin alpha fused to green fluorescent protein was assessed. Fusing prothymosin alpha to green fluorescent protein turned out to be the superior approach resulting in production of high titer anti-prothymosin alpha antibodies. From these studies, two highly specific anti-prothymosin alpha monoclonal antibodies recognizing epitopes within the amino terminal (2F11) and middle (4F4) portions of the human prothymosin alpha molecule were obtained and characterized.