Victrelis (boceprevir) / Roche, Merck (MSD) - LARVOL DELTA

Ligand-based virtual screening to discover potential inhibitors of SARS-CoV-2 main protease. (PubMed, Phys Chem Chem Phys) - "In this work, ∼16 million compounds from various small molecule databases were screened using ligand-based virtual screening (LBVS) with boceprevir as the reference compound to identify new small molecule inhibitors of Mpro...Notably, conformational clustering and FEL analyses depicted hydrogen bond interactions of C3 with Thr26, oxyanion hole residues (Asn142 and Gly143), the catalytic residue (Cys145), and Glu166 of Mpro, suggesting its strong binding affinity and potential inhibitory effect. The integrated computational methodology employed in this work identified promising lead compounds against Mpro activity, which warrants further experimental validation to develop them as antiviral agents against SARS-CoV-2."

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

BOC-HIV: HIV Patients With Chronic Hepatitis C Genotype 1 Infection Who Failed Previously to Peginterferon /Ribavirin (clinicaltrials.gov) - P3 | N=108 | Terminated | Sponsor: Anna Cruceta | Completed ➔ Terminated; Difficulty in patient recruitment

Trial termination • Hepatitis C • Human Immunodeficiency Virus • Infectious Disease • Inflammation • CD4

Harnessing Antiviral Peptides: From Molecular Mechanisms to Clinical Translation. (PubMed, Curr Res Pharmacol Drug Discov) - "Both natural and synthetic AVPs are discussed, including FDA-approved agents such as enfuvirtide (HIV) and boceprevir (HCV), along with candidates currently in clinical trials. AVPs represent a promising class of antiviral agents with the potential to address current therapeutic gaps and improve future outbreak response. This review highlights their growing importance in the field of antiviral therapy and outlines future directions for research and development."

Journal • Review • Human Immunodeficiency Virus • Infectious Disease

The Dynamical Asymmetry in SARS-CoV2 Protease Reveals the Exchange Between Catalytic Activity and Stability in Homodimers. (PubMed, Molecules) - "We analyzed the free form (apo) and compared the results with those coming from the (holo) form bound to the inhibitor Boceprevir, an FDA-approved drug repurposed for COVID-19 therapy...These results highlight a sort of 'symmetry breaking', making a symmetric structure to display functional induced asymmetric behavior in response to a perturbation. This highly coordinated dynamics in response to an external cue confirms the character of 'complex molecular machines' of biopolymers."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

A Comprehensive Review of Antiviral Therapy for Hepatitis C: The Long Journey from Interferon to Pan-Genotypic Direct-Acting Antivirals (DAAs). (PubMed, Viruses) - "When combined with ribavirin, peg-IFN achieved higher SVR rates, especially in non-genotype 1 HCV infections, but the combination also brought additional side effects, such as anemia and depression. The advent of the first-generation DAAs, such as telaprevir and boceprevir, marked a significant milestone...Second-generation DAAs, like sofosbuvir and ledipasvir, introduced IFN-free regimens with improved safety profiles and efficacy. The most recent advances are pan-genotypic DAAs, including glecaprevir-pibrentasvir and sofosbuvir-velpatasvir, which offer high SVR rates across all genotypes, shorter treatment durations, and fewer side effects. Current pan-genotypic regimens represent a cornerstone in HCV therapy, providing an accessible and effective solution globally."

Journal • Review • CNS Disorders • Depression • Hematological Disorders • Hepatitis C • Hepatology • Infectious Disease • Inflammation • Psychiatry

Assessment of repurposed compounds against coronaviruses highlights the antiviral broad-spectrum activity of host-targeting iminosugars and confirms the activity of potent directly acting antivirals. (PubMed, Antiviral Res) - "We observed 13 compounds showing antiviral activity against SARS-CoV-2, including seven FDA-approved compounds (remdesivir, boceprevir, amiloride, nafamostat, cisplatin, silmitasertib, and miglustat), and six compounds in pre-clinical and clinical development (tarloxotinib, lucerastat (NB-DGJ), MON-DNJ, NAP-DNJ, NN-DGJ and NN-DNJ). Its activity also extended to another betacoronavirus HCoV OC43, but not alphacoronavirus HCoV 229E. Our cellular screening results add to the body of knowledge on antivirals against coronaviruses and confirm the antiviral efficacy of iminosugars in cellular assays using the human lung-cell line Calu-3."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Systematic Reevaluation of Repurposed Drugs Against the Main Protease of SARS-CoV-2 via Combined Experiments. (PubMed, J Med Virol) - "Our results from a set of in vitro assays revealed that boceprevir is a potential Mpro inhibitor, but other repurposed drugs, including atazanavir, dipyridamole, entrectinib, ethacridine, glecaprevir, hydroxychloroquine, ivermectin, meisoindigo, pelitinib, raloxifene, roxatidine acetate, saquinavir, teicoplanin, thonzonium bromide, and valacyclovir, are not. Our research highlights that the use of candidate Mpro inhibitors from primary screening warrants further comprehensive studies before the reporting of new findings."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

EARLY NONINVASIVE EVALUATION OF LIVER FIBROSIS AFTER HEPATITIS C TREATMENT: THE IMPACT OF INFLAMMATION. (PubMed, Arq Gastroenterol) - "The evaluation of hepatic elastography by the ARFI method before and after (6 - 9 months) successive treatment of hepatitis C in responders and non-responders led to the conclusion that the reduction of elastography parameters seems to be related to a decrease in hepatic inflammation rather than a reduction in fibrosis per se."

Journal • Fibrosis • Gastroenterology • Hepatitis C • Hepatology • Immunology • Infectious Disease • Inflammation • Liver Cirrhosis

Peptide Aldehydes Incorporating Thiazol-4-yl Alanine Are Potent In Vitro Inhibitors of SARS-CoV-2 Main Protease. (PubMed, ACS Med Chem Lett) - "Continued research efforts have elucidated several peptidic small molecules like GC376, boceprevir, and nirmatrelvir with potent anticoronaviral activity bearing optimized amino acid side chain residues. We synthesized and tested several analogue chimeras of GC376 and boceprevir that have surrogate residues at the P1 and/or P2 position in order to further improve target binding. Both P1 variants with either a nonpolar cyclobutyl or polar thiazol-4-yl alanine resulted in low-micromolar to submicromolar Mpro inhibitors with strong antiviral activity in cell assays."

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

Development of a Biosafety Level 1 Cellular Assay for Identifying Small-Molecule Antivirals Targeting the Main Protease of SARS-CoV-2: Evaluation of Cellular Activity of GC376, Boceprevir, Carmofur, Ebselen, and Selenoneine. (PubMed, Int J Mol Sci) - "Computational analyses of binding energies suggest that noncovalent interactions play a critical role in facilitating the covalent modification of the C145 residue, leading to Mpro inhibition. Our method is straightforward, cost-effective, and readily applicable in standard laboratories, making it accessible to researchers with varying levels of expertise in infectious diseases."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

An orally bioavailable SARS-CoV-2 main protease inhibitor exhibits improved affinity and reduced sensitivity to mutations. (PubMed, Sci Transl Med) - "Inhibitors of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro) such as nirmatrelvir (NTV) and ensitrelvir (ETV) have proven effective in reducing the severity of COVID-19, but the presence of resistance-conferring mutations in sequenced viral genomes raises concerns about future drug resistance...We hypothesized that the covalent hepatitis C virus protease inhibitor boceprevir (BPV) could serve as the basis for orally bioavailable drugs that inhibit SARS-CoV-2 Mpro more efficiently than existing drugs...Last, ML2006a4 was found to be less sensitive to several mutations that cause resistance to NTV or ETV and occur in the natural SARS-CoV-2 population. Thus, anticipatory design can preemptively address potential resistance mechanisms to expand future treatment options against coronavirus variants."

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

In silico study of inhibition activity of boceprevir drug against 2019-nCoV main protease. (PubMed, Z Naturforsch C J Biosci) - "The optimum binding location has been considered for molecular dynamics simulation. The findings have been addressed to clarify the boceprevir drug efficacy against the 2019-nCoV M."

Journal • Infectious Disease • Novel Coronavirus Disease

Landscape of In Silico Tools for Modeling Covalent Modification of Proteins: A Review on Computational Covalent Drug Discovery. (PubMed, J Phys Chem B) - "However, there has been a resurgence in covalent drug design following the success of several covalent drugs such as boceprevir (2011), ibrutinib (2013), neratinib (2017), dacomitinib (2018), zanubrutinib (2019), and many others. In this report, we review a set of recent publications that focused on developing and/or implementing novel in silico techniques in "Computational Covalent Drug Discovery (CCDD)". We also discuss the advantages and disadvantages of these approaches along with what improvements are required to make it a great tool in medicinal chemistry in the near future."

Journal • Review

Computational Screening Using a Combination of Ligand-Based Machine Learning and Molecular Docking Methods for the Repurposing of Antivirals Targeting the SARS-CoV-2 Main Protease. (PubMed, Daru) - "Results demonstrated the efficiency of LBVS combined with MD. This combined strategy provided positive evidence showing that the top screened drugs, including CCX-140, which had the lowest MD score, can be reasonably advanced to the in vitro phase. This combined method may accelerate the discovery of therapies for novel or orphan diseases from existing drugs."

Journal • Machine learning • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Structure-based development and preclinical evaluation of the SARS-CoV-2 3C-like protease inhibitor simnotrelvir. (PubMed, Nat Commun) - "The structure-based optimization of boceprevir, an approved HCV protease inhibitor, leads to identification of simnotrelvir that covalently inhibits SARS-CoV-2 3CL with an enthalpy-driven thermodynamic binding signature. It effectively blocks replications of SARS-CoV-2 variants in cell-based assays and exhibits good pharmacokinetic and safety profiles in male and female rats and monkeys, leading to robust oral efficacy in a male mouse model of SARS-CoV-2 Delta infection in which it not only significantly reduces lung viral loads but also eliminates the virus from brains. The discovery of simnotrelvir thereby highlights the utility of structure-based development of marked protease inhibitors for providing a small molecule therapeutic effectively combatting human coronaviruses."

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

Molecular Mechanisms of Resistance to Direct-Acting Antiviral (DAA) Drugs for the Treatment of Hepatitis C Virus Infections. (PubMed, Diagnostics (Basel)) - "L2003V, Q2002H, M2000T, Y2065N, and NL2003M of NS5A and L2003M of NS5B conferred resistance to daclatasvir. S2702T NS5B was the sofosbuvir-resistant variant...The double-drug resistant variants R1181K (faldaprevir and asunaprevir), A1182V and Q1106K/R (faldaprevir and simeprevir), T1080S (faldaprevir and telaprevir), and single drug-resistant variants V1062L (telaprevir), D1194E/T (simeprevir), D1194G (asunaprevir), S1148A/G (simeprevir), and Q1106L (Boceprevir) of NS3/4A were determined. The molecular phenomenon of DAA resistance is paramount in the development of HCV drug candidates. RAASs in NS3, NS5A, and NS5B reduce the susceptibility to DAAs; therefore, continuous RAAS-dependent resistance profiling in HCV is recommended to minimize the probability of DAA therapeutic failure."

Journal • Hepatitis C • Hepatology • Infectious Disease • Inflammation

Substitutions in SARS-CoV-2 Mpro Selected by Protease Inhibitor Boceprevir Confer Resistance to Nirmatrelvir. (PubMed, Viruses) - "Structural analysis of Mpro suggested that A173V can cause resistance by making boceprevir and nirmatrelvir binding less favorable. This study contributes to a comprehensive overview of the resistance profile of the first-in-line COVID-19 treatment nirmatrelvir and can thus inform population monitoring and contribute to pandemic preparedness."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Rational design of covalent and non-covalent SARS-CoV-2 main protease inhibitors (ACS-Fall 2023) - "Currently, there are three FDA-approved antiviral drugs, remdesivir, molnupiravir, and paxlovid...We initially discovered GC376, calpain inhibitors II and XII, and boceprevir as dual inhibitors of Mpro and host cathepsin L from a screening of a protease inhibitor library...Lastly, we introduce recent progress in identifying naturally occurring Mpro mutants that are resistant to nirmatrelvir from genome mining of the nsp5 sequences deposited in the GISAID database. Collectively, the covalent and noncovalent Mpro inhibitors and the nirmatrelvir-resistant hot spot residues from our studies provide insightful guidance for future work aimed at developing orally bioavailable Mpro inhibitors that do not have overlapping resistance profile with nirmatrelvir."

Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • SPECC1

Evaluation of SARS-CoV-2 main protease inhibitors utilizing X-ray crystallography (ACS-Fall 2023) - "Boceprevir was another inhibitor that showed potency against the SARS-CoV-2 MPro and contains an α-ketoamide warhead, a P1 β-cyclobutylalanyl moiety, a P2 dimethylcyclopropylproline, a P3 tert-butylglycine, and a P4 N-terminal tert-butylcarbamide...As a novel covalent modification, this cross-link serves potentially as a redox switch to regulate the catalytic activity of MPro, a demonstrated drug target of COVID-19. The formation of this linkage leads to a much more open active site that can potentially be targeted for the development of novel SARS-CoV-2 antivirals."

Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

A suitable drug structure for interaction with SARS-CoV-2 main protease between boceprevir, masitinib and rupintrivir; a molecular dynamics study. (PubMed, Arab J Chem) - "According to the docking results, binding energy for boceprevir, masitinib and rupintrivir with CMP are -10.80, -9.39, and -9.51 kcal/mol respectively. Also, for all investigated systems, van der Waals and electrostatic interactions are quite favorable for binding the drugs to SARS-CoV-2 coronavirus main protease, indicating confirmation of the complex stability."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Recent Advances in Covalent Drug Discovery. (PubMed, Pharmaceuticals (Basel)) - "The successful approval of some covalent protein kinase inhibitors, such as ibrutinib (BTK covalent inhibitor) and dacomitinib (EGFR covalent inhibitor), and the very recent discovery of covalent inhibitors for viral proteases, such as boceprevir, narlaprevir, and nirmatrelvir, represent a new milestone in covalent drug development. Furthermore, covalent inhibitors are becoming more and more common in proteolysis, targeting chimeras (PROTACs) for degrading proteins, including those that are currently considered to be 'undruggable'. The aim of this review is to highlight the current state of covalent inhibitor development, including a short historical overview and some examples of applications of PROTAC technologies and treatment of the SARS-CoV-2 virus."

Journal • Review • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • Targeted Protein Degradation • EGFR

Utilization, Reimbursements and Prices Trends of Hepatitis C Virus Drugs in the US Medicaid Programs from 2001 to 2021 (ISPOR 2023) - "The study evaluated all medications authorized for HCV treatment in the US, such as ribavirin (RBV), pegylated interferon alfa-2a (PEG-INFA2a), and DAA brand and generics (e.g., Boceprevir, Telaprevir, Simeprevir, Sofosbuvir, Ledipasvir/Sofosbuvir, Elbasvir/Grazoprevir, Daclatasvir, Sofosbuvir/Velpatasvir, and Glecaprevir/Pibrentasvir). Despite the introduction of multiple DAAs agents, the drug prices remained high and unchanged during the study period. The increase in HCV incidence cases in recent years indicates accessibility issues for costly and effective DAAs medications."

Medicaid • Reimbursement • US reimbursement • Hepatitis C • Hepatology • Infectious Disease • Inflammation

Orthogonal dual reporter-based gain-of-signal assay for probing SARS-CoV-2 3CL protease activity in living cells: inhibitor identification and mutation investigation. (PubMed, Emerg Microbes Infect) - "Except for the approved drug PF-07321332, only five of these inhibit 3CLpro in our assays: GC376; PF-00835231; S-217622; Boceprevir; and Z-FA-FMK. Three mutants were identified as being less susceptible to PF-07321322 (P132H) and S-217622 (G15S, T21I). This assay should greatly facilitate the development of novel 3CLpro-targeted drugs and the monitoring of the susceptibility of emerging SARS-CoV-2 variants to 3CLpro inhibitors."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

In silico identification and molecular dynamic simulations of derivatives of 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide against main protease 3CL of SARS-CoV-2 viral infection. (PubMed, J Mol Model) - "Docking simulations were performed by using a combination of empirical free energy force field with a Lamarckian genetic algorithm under AutoDock 4.2. By the application of AMBER14 force field and SPCE water model, molecular dynamic simulations and MM-PBSA were calculated for 100 ns."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Bias-force guided simulations combined with experimental validations towards GPR17 modulators identification. (PubMed, Biomed Pharmacother) - "The external bias-potentials were then applied to the screened hits during the MD simulations which enabled to predict a spectrum of rupture peak force values that were used to select four approved drugs -ZINC000003792417 (Sacubitril), ZINC000014210457 (Victrelis), ZINC000001536109 (Pralatrexate) and ZINC000003925861 (Vorapaxar)- as top hits. Small interference of the RNA (siRNA)- silenced the GPR17 to further validate the targeted binding of Sacubitril with GPR17. In the current investigation, we have identified new repurposable GPR17 specific drugs which are likely to increase the opportunity to treat orphan deadly diseases."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor