Ganovo (danoprevir) / Roche, Ascletis, Pfizer - LARVOL DELTA

Drug Solubility in Human Colonic Fluids and Comparison to Small Intestinal and Simulated Fluids. (PubMed, Mol Pharm) - "Therefore, this study aimed to measure and compare the apparent solubility of eight drugs with varying physicochemical properties (apixaban, danoprevir, dexloxiglumide, febuxostat, fenofibrate, rofleponide, ticagrelor and tofacitinib) in pooled aspirates from the proximal human colon and small intestine, along with simulated media and buffers commonly used in solubility assessment. Solubilities of all other drugs were predicted reasonably well in blank buffers and simulated media. The results generated in this study may serve as reference data for the validation of improved in vitro and in silico tools for colonic drug solubility prediction."

Journal • Gastrointestinal Disorder

D-Cycloserine, a potential candidate for reducing hepatitis B virus cccDNA in vitro. (PubMed, J Virol Methods) - "Among them, several chemicals including danoprevir, L- and D-cycloserine, phenytoin sodium, amantadine, and germacrone showed a decrease in cccDNA levels. Especially, D-cycloserine diminished the secretion of HBV antigens and induced cccDNA degradation in the HBV infection system. This screening system helps to develop the therapeutic drug target to cccDNA This screening system may help develop therapeutic drugs targeting cccDNA."

Journal • Preclinical • Fibrosis • Hepatitis B • Hepatitis C • Hepatocellular Cancer • Hepatology • Immunology • Infectious Disease • Inflammation • Oncology • Solid Tumor

Drugs and natural products for the treatment of COVID-19 during 2020, the first year of the pandemic. (PubMed, Bol Med Hosp Infant Mex) - "These include some that are not considered anti-inflammatory, such as Aviptadil, pyridostigmine bromide, anakinra, imatinib, baricitinib, and bevacizumab, as well as the combination of ivermectin, aspirin, dexamethasone, and enoxaparin...On the other hand, tofacitinib, novaferon with ritonavir, and lopinavir were also effective, as well as in combination with antiviral therapies such as danoprevir with ritonavir. The natural products colchicine and Vitamin D3 were only effective in patients with mild-to-moderate COVID-19, as was hydroxychloroquine. Drug repositioning has been the main tool in the search for effective therapies by expanding the pharmacological options available to patients."

Journal • Infectious Disease • Inflammation • Novel Coronavirus Disease • Respiratory Diseases

Comparative efficacy and safety of Sofosbuvir/Velpatasvir and Danoprevir for the treatment of chronic hepatitis C: the real-world data in China. (PubMed, BMC Gastroenterol) - "In this retrospective real-world study, the efficacy of DNV combined therapy is similar to Sofosbuvir/Velpatasvir ± Ribavirin for chronic HCV infection, and the safety is comparable. DNV based therapy is a promising regimen for chronic hepatitis C."

Journal • Real-world • Real-world evidence • Fibrosis • Hepatitis C • Hepatology • Immunology • Infectious Disease • Inflammation • AFP

HCV antiviral drugs have the potential to adversely perturb the maternal-fetal communication axis through inhibition of CYP3A7 DHEA-S oxidation. (PubMed, Drug Metab Dispos) - "Furthermore, paritaprevir, asunaprevir, simeprevir, danoprevir, and glecaprevir all had observed half-maximal inhibitory concentrations between the range of 10-20 µM, which is physiologically relevant in comparison to the K of DHEA-S oxidation (reported to be between 5 to 20 µM). We discovered that five HCV antivirals inhibited DHEA-S metabolism by CYP3A7, and paritaprevir inactivated the enzyme. Our studies demonstrate the potential threat these drugs pose to proper fetal development."

Journal • Hepatitis C • Hepatology • Infectious Disease • Inflammation • CYP3A7

A Standardized Set of MoClo-Compatible Inducible Promoter Systems for Tunable Gene Expression in Yeast. (PubMed, ACS Synth Biol) - "To address this, we created the yeast Tunable Expression Systems Toolkit (yTEST), which contains a set of five extensively characterized inducible promoter systems regulated by the small-molecules doxycycline (Dox), abscisic acid (ABA), danoprevir (DNV), 1-naphthaleneacetic acid (NAA), and 5-phenyl-indole-3-acetic acid (5-Ph-IAA). Furthermore, each of the five classes of systems could be induced at least 60-fold after a 6 h induction and the highest fold change observed was approximately 300. Thus, yTEST provides a reliable, diverse, and customizable set of inducible promoters to modulate gene expression in yeast for applications in synthetic biology, metabolic engineering, and basic research."

Journal

Cheminformatics-Based Study Identifies Potential Ebola VP40 Inhibitors. (PubMed, Int J Mol Sci) - "A total of 23 approved drugs, including doramectin, glecaprevir, velpatasvir, ledipasvir, avermectin B1, nafarelin acetate, danoprevir, eltrombopag, lanatoside C, and glycyrrhizin, among others, were also predicted to have potential anti-EBOV activity and can be further explored so that they may be repurposed for EVD treatment. Molecular dynamics simulations coupled with molecular mechanics Poisson-Boltzmann surface area calculations corroborated the stability and good binding affinities of the complexes (-46.97 to -118.9 kJ/mol). The potential lead compounds may have the potential to be developed as anti-EBOV drugs after experimental testing."

Journal • Hematological Disorders • Infectious Disease

Identification of host genomic biomarkers from multiple transcriptomics datasets for diagnosis and therapies of SARS-CoV-2 infections. (PubMed, PLoS One) - "This analysis resulted in the identification of top-ranked ten drug agents, including Nilotinib, Tegobuvir, Digoxin, Proscillaridin, Olysio, Simeprevir, Hesperidin, Oleanolic Acid, Naltrindole and Danoprevir. Finally, we investigated the binding stability of the top-ranked three drug molecules Nilotinib, Tegobuvir and Proscillaridin with the three top-ranked proposed receptors (AURKA, AURKB, OAS1) by using 100 ns MD-based MM-PBSA simulations and observed their stable performance. Therefore, the findings of this study might be useful resources for diagnosis and therapies of SARS-CoV-2 infections."

Biomarker • Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • AURKA • AURKB • ER • IL6 • MEIS1 • MIR106B • MIR20A • MIR20B • MIR93 • MMP2 • PBX1 • STAT4

All-oral, 12-week ravidasvir plus ritonavir-boosted danoprevir and ribavirin delivers 100% svr12 in treatment-naive non-cirrhotic hcv genotype 1 patients with resistance-associated substitutions of a phase 2/3 clinical trial in china (EASL-ILC 2019) - P2, P2/3; "For Chinese treatment-naïve non-cirrhotic GT1 HCV adult patients, there was no significant impact of baseline NS5A RASs on SVR12 with 12-week ravidasvir plus ritonavir-boosted danoprevir and ribavirin."

Clinical • P2/3 data • Fibrosis • Hepatitis C • Hepatology • Immunology

A fuzzy logic-based computational method for the repurposing of drugs against COVID-19. (PubMed, Bioimpacts) - "According to the findings, ribavirin, simeprevir, danoprevir, and XTL-6865 may be helpful in controlling the disease. It can be concluded that the similarity-based drug repurposing techniques may be the most suitable option for managing emerging diseases such as COVID-19 and can be applied to a wide range of data. Also, fuzzy logic-based scoring methods can produce outcomes which are more consistent with the real-world biological applications than others."

Journal • Hepatitis C • Hepatology • Infectious Disease • Inflammation • Novel Coronavirus Disease • Respiratory Diseases

Identification of host transcriptome-guided repurposable drugs for SARS-CoV-1 infections and their validation with SARS-CoV-2 infections by using the integrated bioinformatics approaches. (PubMed, PLoS One) - "We also detected some chemicals (Valproic Acid, Cyclosporine, Copper Sulfate and arsenic trioxide) that may regulates HubGs...We found Rapamycin, Tacrolimus, Torin-2, Radotinib, Danoprevir, Ivermectin and Daclatasvir as the top-ranked 7 candidate-drugs with respect to our proposed target proteins for the treatment against SARS-CoV-1 infections...Finally, we validated all of our findings by the literature review. Therefore, the proposed candidate-drugs might play a vital role for the treatment against different variants of SARS-CoV-2 infections with comorbidities, since the proposed HubGs are also associated with several comorbidities."

Journal • Infectious Disease • Novel Coronavirus Disease • Oncology • Pulmonary Disease • Respiratory Diseases • BIRC3 • ETS1 • FOXC1 • GATA2 • MIR106B • MIR155 • MIR19B1 • MIR34A • MIR92A1 • RIPK1 • SIRT1 • SMAD4 • TP53

Repurposing of FDA-approved drugs as potential inhibitors of the SARS-CoV-2 main protease: Molecular insights into improved therapeutic discovery. (PubMed, Comput Biol Med) - "Among 53 shortlisted drugs with binding energies lower than that of the crystal-bound inhibitor α-ketoamide 13 b (-6.7 kcal/mol), velpatasvir, glecaprevir, grazoprevir, baloxavir marboxil, danoprevir, nelfinavir, and indinavir (-9.1 to -7.5 kcal/mol) were the most significant on the list (hereafter referred to as the 53-list). Hence, theoretical pK (K = inhibitor constant) values for all 53 drugs were provided. Notably, ΔG directly correlates with the average distance of the drugs from the His41-Cys145 catalytic dyad of Mpro, providing a roadmap for rapid screening and improving the inhibitor design against SARS-CoV-2 Mpro."

FDA event • Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Finding a prospective dual-target drug for the treatment of coronavirus disease by theoretical study. (PubMed, J Biomol Struct Dyn) - "The simulation results showed that 10 ligands from 28 ligands were separated from the RBD domain, and among 18 remained ligands, baloxavir marboxil, and danoprevir drugs, besides endonuclease activity and protease inhibitory, can bind to key residues of the RBD domain. Then these drugs have a dual target and should be more effective than current drugs, and experimental studies should be done on baloxavir marboxil and danoprevir as more potential drugs for coronavirus disease Communicated by Ramaswamy H. Sarma."

Clinical • Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Inhibitory activity of limonoids from Khaya grandifoliola C.DC (Meliaceae) against hepatitis C virus infection in vitro. (PubMed, Avicenna J Phytomed) - "In the replication step, the limonoids decreased the expression of NS5B similar to danoprevir. These compounds also significantly decreased but up-regulated the expression of Class-III phosphatidylinositol 4-kinase alpha and 2',5'-oligoadenylate synthase-3, respectively. The present findings suggest that limonoids from K. grandifoliola are potential anti-HCV agents and may offer an advantage in the treatment of HCV infection."

Journal • Preclinical • Hepatitis C • Hepatology • Infectious Disease • Inflammation

Pharmacokinetics, safety and tolerability of ravidasvir, with and without danoprevir/ritonavir, in healthy subjects. (PubMed, Antimicrob Agents Chemother) - "Both single and multiple doses of RDV with or without DNVr were well tolerated. The favorable pharmacokinetic and safety results support ravidasvir's continued clinical development and treatment."

Clinical • Journal • PK/PD data • Hepatitis C • Hepatology • Infectious Disease • Inflammation

C-DIAMOND: Effectiveness and Safety of Direct-Acting Antiviral Agents for the Treatment of Chronic Hepatitis C (clinicaltrials.gov) - P; N=300; Recruiting; Sponsor: Qing XIe

Clinical • New trial • Real-world evidence • Hepatitis C • Hepatology • Infectious Disease • Inflammation

Hepatitis C Virus Protease Inhibitors Show Differential Efficacy and Interactions with Remdesivir for Treatment of SARS-CoV-2 in Vitro. (PubMed, Antimicrob Agents Chemother) - "Linear PI boceprevir, telaprevir and narlaprevir had 50% effective concentrations (EC50) of ∼40 μM. Among macrocyclic PI, simeprevir had the highest (EC50 15 μM) and glecaprevir the lowest (EC50 >178 μM) potency, with paritaprevir, grazoprevir, voxilaprevir, vaniprevir, danoprevir and deldeprevir in between. Acyclic PI asunaprevir and faldaprevir had EC50 of 72 and 23 μM, respectively...Viral suppression was achieved with 3- to 8-fold EC50 boceprevir or 1-fold EC50 simeprevir or grazoprevir, but not boceprevir, in combination with 0.4- to 0.8-fold EC50 remdesivir; these concentrations did not lead to viral suppression in single treatments. This study could inform development and application of protease inhibitors for optimized antiviral treatments of COVID-19."

Journal • Preclinical • Gastrointestinal Cancer • Hepatitis C • Hepatocellular Cancer • Hepatology • Infectious Disease • Inflammation • Liver Cancer • Lung Cancer • Novel Coronavirus Disease • Oncology • Respiratory Diseases • Solid Tumor

Efficacy and safety of danoprevir plus sofosbuvir in GT 1, 2, 3, or 6 chronic hepatitis C patients with or without cirrhosis in China. (PubMed, Medicine (Baltimore)) - "All-oral direct-acting antiviral therapies are becoming the choice for hepatitis C (HCV) treatment. No serious event was observed during the treatment and follow-up. Only 5 patients had mild adverse events.DNVr plus sofosbuvir ± ribavirin for 12 weeks provided 100% SVR12 in a broad patient population and were well tolerated, which may be a promising regimen for CHC treatment."

Clinical • Journal • Fibrosis • Hepatitis C • Hepatology • Immunology • Infectious Disease • Inflammation

The serine peptidase inhibitor N-ρ-tosyl-l-phenylalanine chloromethyl ketone (TPCK) affects the cell biology of Candida haemulonii species complex. (PubMed, Fungal Biol) - "Initially, eight distinct SPIs (phenylmethylsulfonyl fluoride - PMSF, 4-(2-aminoethyl) benzenesulfonyl fluoride hydrochloride - AEBSF, N-α-tosyl-l-lysine chloromethyl ketone hydrochloride - TLCK, N-p-tosyl-l-phenylalanine chloromethyl ketone - TPCK, simeprevir, boceprevir, danoprevir and telaprevir) were tested on the fungal growth. In addition, the 24 h-treatment of the mature biofilm promoted a decrease in biomass, viability and extracellular matrix. Altogether, our results highlight that SPIs may be promising new therapeutic agents in the treatment of candidiasis caused by emergent, opportunistic and MDR species forming the C. haemulonii complex."

Journal • Candidiasis

Evaluation of Ganovo （Danoprevir ） Combined With Ritonavir in the Treatment of Novel Coronavirus Infection (clinicaltrials.gov) - P4; N=50; Recruiting; Sponsor: The Ninth Hospital of Nanchang

Clinical • New P4 trial • Infectious Disease • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases

Molecular modeling evaluation of the binding effect of five protease inhibitors to COVID-19 main protease. (PubMed, Chem Phys) - "In this work, the binding mechanisms of five protease inhibitors (e.g., danoprevir, darunavir, ASC09, lopinavir and ritonavir) to COVID-19 M were investigated. It is found that most of the selected drug molecules bind stably to the COVID-19 M from the molecular dynamics simulation. Moreover, the MM/PBSA free energy calculations suggest that lopinavir with positive charge might be most active against COVID-19 M."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

OATP1B1/1B3-mediated hepatic uptake determines the pharmacokinetics of large lipophilic acids: In vitro-in vivo evaluation in cynomolgus monkey. (PubMed, J Pharmacol Exp Ther) - "Intravenous pharmacokinetics of 16 compounds, with molecular weight ~400-730 Da, logP ~3.5-8 and acid pKa <6, were obtained in cynomolgus monkey following dosing without and with a single-dose rifampicin-OATP1B1/1B3 probe inhibitor...Additionally, clearance of danoprevir was reduced by about 35%, although statistical significance was not reached...OATP1B1/1B3-mediated hepatic uptake is of key importance in the pharmacokinetics and drug-drug interactions of almost all drugs and new molecular entities in this space. Diligent in vitro and in vivo transport characterization is needed to avoid the false negatives often noted due to general limitations in the in vitro assays while handling compounds with such physicochemical attributes."

Journal • PK/PD data • Preclinical • Hepatology

Evaluating the role of macrocycles in the susceptibility of hepatitis C virus NS3/4A protease inhibitors to drug resistance (ACS Chem Biol) - PMID: 23594083; "Macrocyclic inhibitors were generally more potent ...the P1-P3 macrocyclic inhibitors were less susceptible to drug resistance than the linear and P2-P4 macrocyclic analogues. In addition, the heterocyclic moiety at P2 largely determined the inhibitor resistance profile, susceptibility to drug resistance, and the extent of modulation by the helicase domain."

Preclinical • Hepatitis C Virus

First clinical study using HCV protease inhibitor danoprevir to treat COVID-19 patients. (PubMed, Medicine (Baltimore)) - "Our findings suggest that repurposing danoprevir for COVID-19 is a promising therapeutic option."

Clinical • Journal • Hepatitis C Virus • Hepatology • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

[VIRTUAL] Capturing Clinician’s Experiences Repurposing Drugs to Inform Future Studies During COVID-19 (IDWeek 2020) - " As of submission, lopinavir-Ritonavir (n=51) was the most commonly reported drug used. The following were also reported: hydroxychloroquine (n=31), azithromycin (n=28), arbidol (n=22), interferon alfa-2B (n=18), moxifloxacin (n=18), methylprednisolone (n=17), ivermectin (n=14), lopinavir (n=12), oseltamivir (n=12). The other drugs reported were danoprevir-ritonavir, intravenous immunoglobulins, interferon, interferon alfa, and tocilizumab... Several drugs are being repurposed to treat COVID-19. CURE ID gives clinicians an opportunity to share their treatment experiences and discuss their questions with a global community of healthcare providers. By utilizing the CURE ID platform, in conjunction with data gathered from other registries, observational studies and clinical trials, hypotheses can be generated that may inform future clinical trials and ultimately, potentially find safe and effective treatments for this deadly disease."

Clinical • Infectious Disease • Novel Coronavirus Disease