grazoprevir (MK-5172) / Merck (MSD) - LARVOL DELTA

Molecular chameleons adaptability in target binding (ACS-Fall 2025) - "Due to their flexible structure, these modalities often behave like molecular chameleons, which have been shown to be important for bioavailability since they can change their conformations based on the polarity of their solvation environment.In this presentation, we will showcase our exploration of the conformational adaptability in target binding of three known molecular chameleons, paritaprevir, grazoprevir, and simeprevir, by evaluating their experimentally determined microcrystal electron diffraction (MicroED) structures, solution-state conformations from NMR spectroscopy, and target-bound structures, in molecular docking studies. This offers a framework for optimizing drug selectivity and improving therapeutic efficacy. Furthermore, it provides a pathway toward rationalizing drug optimization for molecular chameleons, facilitating the safe use of these inhibitors while broadening their potential in antiviral and cancer-target applications."

Infectious Disease • Respiratory Diseases

Molecular chameleons adaptability in target binding. (PubMed, Struct Dyn) - "In this study, we explore the conformational adaptability in target binding of the three known molecular chameleons, paritaprevir, grazoprevir, and simeprevir, by docking their experimental crystal structures, solution conformations, and target-bound structures into multiple protein targets, including human drug transporters associated with drug-drug interactions and COVID-19 related proteins. Our findings reveal that the macrocyclic core conformational class, or "chameleonic group," determines the overall pharmacophore conformations and influences the conformational changes required for binding to various proteins. These insights provide a pathway toward rationalizing drug optimizations for molecular chameleons as well as offering specific guidance for improving Hepatitis C virus nonstructural protein 3/4A inhibitors, including providing a starting point for their COVID-19 repurposing and cancer therapy."

Journal • Hepatitis C • Infectious Disease • Novel Coronavirus Disease • Oncology

Rational Design and Relative Bioperformance of High Drug Load Grazoprevir Amorphous Nanoparticle Formulations. (PubMed, Pharm Dev Technol) - "The 45/45/10 GZP/HPMCAS-L/SLS nanoparticle formulation and the amorphous dispersion formulation were evaluated in a dog PK study, with the 45/45/10 GZP/HPMCAS-L/SLS formulation provided equivalent PK. These results highlight the potential benefit of directly designed nanoparticle formulations to maximize formulation bioperformance at higher drug loadings or to enable smaller dosage forms."

Journal

Development of a chemically induced dissociation system via phage surface-displayed nanobody screening. (PubMed, FEBS Lett) - "By employing Grazoprevir as a chemical disruptor of the NS3a/nanobody interaction, we demonstrate that our chemically induced dissociation system (CIDiss) can effectively regulate protein-protein interaction in the endoplasmic reticulum in human cells...Impact statement Here, we describe a novel chemically-induced dissociation (CIDiss) system which can effectively and safely regulate protein-protein interaction in the endoplasmic reticulum in human cells. This enhances the safety profile of cell-based therapies, which has potential for medical applications and also offers a versatile tool for dissecting and modulating protein-protein interactions."

Journal • Hepatitis C • Infectious Disease • Inflammation

On-demand treatment of metabolic diseases by a synthetic drug-inducible exocytosis system. (PubMed, Nat Commun) - "StimExo also mediated insulin exocytosis using a cell-based gene delivery strategy in vivo, accounting for real-time control of blood glucose homeostasis in male diabetic mice in response to the FDA-approved drug grazoprevir. This study achieves true "sense-and-respond" cell-based therapies and provides a platform for remote control of in vivo transgene activities using various trigger signals of interest."

Journal • Metabolic Disorders

Development of an OATP1-humanized transchromosomic mouse model for prediction of hepatic drug uptake in humans. (PubMed, Drug Metab Dispos) - "Rifampicin (60 mg/kg orally) increased the area under the plasma concentration-time curves of orally administered pitavastatin and grazoprevir in hOATP1-MAC mice, but not of asunaprevir. SIGNIFICANCE STATEMENT: Transchromosomic technology holds promise for addressing species differences by introducing multiple solute carrier drug transporter genes such as OATP1. Mice OATP1-humanized using a mouse artificial chromosome vector demonstrated enhanced clearance of endogenous OATP1B biomarkers and probe drugs."

Journal • Preclinical • ATP1A1 • SLCO1A2 • SLCO1B3 • SLCO1C1

Elucidating Contributions of Drug Transporters/Enzyme to Nonlinear Pharmacokinetics of Grazoprevir by PBPK Modeling With a Cluster Gauss-Newton Method. (PubMed, CPT Pharmacometrics Syst Pharmacol) - "By estimating the extent of saturation for each molecule in the liver and intestine and conducting sensitivity analyses of the Km values, it was inferred that OATP1B3 contributed the most to the nonlinearity of plasma GZR concentrations, followed by P-gp. In conclusion, the PBPK-CGNM, supplemented by penalized in vitro parameters, was shown to be effective for analyzing complex pharmacokinetics involving drug transporters and enzymes."

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

A trigger-inducible split-Csy4 architecture for programmable RNA modulation. (PubMed, Nucleic Acids Res) - "Inspired by these results, we went on to use such split-Csy4 module to engineer inducible CRISPR- and translation-level gene switches regulated by the FDA-approved drug grazoprevir. This work provides valuable resource for Csy4-related biomedical research and discusses important issues for the development of clinically eligible regulation tools."

Journal

STRAIGHT-IN Dual: a platform for dual, single-copy integrations of DNA payloads and gene circuits into human induced pluripotent stem cells. (PubMed, bioRxiv) - "Furthermore, we designed a grazoprevir-inducible synZiFTR system to complement the widely-used tetracycline-inducible system, providing independent, tunable, and temporally controlled expression of both transcription factors and functional reporters. The unprecedented efficiency and speed with which STRAIGHT-IN Dual generates homogenous genetically engineered hiPSC populations represents a major advancement for synthetic biology in stem cell applications and opens opportunities for precision cell engineering."

Journal

Drugs for hepatitis C virus infection. (PubMed, Med Lett Drugs Ther) - No abstract available

Journal • Addiction (Opioid and Alcohol) • Hepatitis C • Hepatology • Infectious Disease • Inflammation

Table 3: Some drug interactions with DAAs for HCV infection. (PubMed, Med Lett Drugs Ther) - No abstract available

Journal • Hepatitis C • Hepatology • Infectious Disease • Inflammation

Figure 1: Treatment of hepatitis C virus infection in treatment-naive adults. (PubMed, Med Lett Drugs Ther) - No abstract available

Journal • Hepatitis C • Hepatology • Infectious Disease • Inflammation

The importance of surface composition and wettability on the dissolution performance of high drug loading amorphous dispersion formulations. (PubMed, J Pharm Sci) - "Using grazoprevir and hypromellose acetate succinate as model drug and polymer respectively, the interplay between particle surface composition, particle wettability, and release performance was investigated...Particles with good wettability showed improved drug release relative to particles that did not wet well, even with similar drug loadings. These observations underscore the intricate interplay between particle wettability and performance in amorphous dispersion formulations and illustrate a promising hierarchical particle approach to formulate high drug loading amorphous dispersions with improved dissolution performance."

Journal

Insilico assessment of hesperidin on SARS-CoV-2 main protease and RNA polymerase: Molecular docking and dynamics simulation approach. (PubMed, Biochem Biophys Rep) - "Absorption, Distribution, Metabolism, Excretion, And Toxicity (ADMET) analysis was performed to compare Hesperidin and Grazoprevir as potential antiviral medicines, evaluating both herbal and chemical ligand results...Compared to RNA polymerase, Mpro showed a greater affinity for bonding with Hesperidin. van der Waals and electrostatic energies dominated, creating a stable Hesperidin-Mpro and Hesperidin-RNA polymerase complex."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Delivery of Large Gene Circuits In Vivo Using an Engineered Baculovirus Vector for Multifactorial Control of Therapeutic Gene Expression (ASGCT 2024) - "Finally, we demonstrate two orthogonal small molecule inducible systems (grazoprevir and tamoxifen) delivered by baculovirus in vivo. Our findings will demonstrate the usefulness of complex regulation for the gene therapy field, as well as the utility of the baculovirus as a therapeutic vector."

Preclinical • Gene Therapies

Drug-Controlled Anti-PD-1 CAR T-Cells to Target the Replication-Competent Reservoir in Tfh Cells (CROI 2024) - "The rapid depletion of TFH sanctuary site in GC while on ART offered the potential to an important advance in the quest for HIV cure if we could develop a second-generation product that had less off target long tern effects.Towards these ends, we integrated a Hepatitis C virus-derived non-structural protein 3 (NS3)-based ON switch into the intracellular domain of our anti-PD-1 CAR (NS3) T cell platform that can be controlled exogenously by administration of a NS3-specific protease inhibitor Grazoprevir (GZV).Mechanistically, the NS3 domain undergoes autocleavage in absence of GZV, thus abrogating any CAR signaling and CAR T cell function. Combined, these data indicate that a drug-controlled anti-PD-1 CAR NS3 is highly functional and can be controlled exogenously through administration or withdrawal of GZV. These data warrant further investigation of drug controlled-anti-PD-1 CAR T cells in ART-treated SIVmac239-infected rhesus macaques to transiently deplete TFH cells to..."

CAR T-Cell Therapy • IO biomarker • Hepatitis C • Hepatology • Human Immunodeficiency Virus • Infectious Disease • Inflammation • CD4 • CD8 • IFNG

Engineered poly(A)-surrogates for translational regulation and therapeutic biocomputation in mammalian cells. (PubMed, Cell Res) - "To exemplify disease treatments that require on-demand drug secretion, we show that a custom-designed gene switch triggered by the FDA-approved drug grazoprevir can effectively control insulin expression and restore glucose homeostasis in diabetic mice. For diseases that require instantaneous sense-and-response treatment programs, we create highly specific sensors for various subcellularly (mis)localized protein markers (such as cancer-related fusion proteins) and show that translation-based protein sensors can be used either alone or in combination with other cell-state classification strategies to create therapeutic biocomputers driving self-sufficient elimination of tumor cells in mice. This design strategy demonstrates unprecedented flexibility for translational regulation and could form the basis for a novel class of programmable gene therapies in vivo."

Journal • Gene Therapies • Oncology • EIF4E • EIF4G1

Mechanisms and Clinical Significance of Pharmacokinetic Drug Interactions Mediated by FDA and EMA-approved Hepatitis C Direct-Acting Antiviral Agents. (PubMed, Clin Pharmacokinet) - "Important DDIs perpetrated by current DAAs include increases in the pharmacokinetic exposure to statins and dabigatran...Conversely, DAAs are victims of DDIs mediated by cyclosporin, ketoconazole, omeprazole and HIV antiretroviral drug combinations, especially when boosted by ritonavir and, to a lesser extent, cobicistat. In addition, concurrent administration of inducers, such as rifampicin, carbamazepine and efavirenz, decreases exposure to some DAAs. Drug-drug interactions that increase the accumulation of HCV N3/4A-protease inhibitors like grazoprevir may exacerbate hepatic injury in HCV patients."

European regulatory • FDA event • Journal • PK/PD data • Review • Hepatitis C • Hepatology • Human Immunodeficiency Virus • Infectious Disease • Inflammation • Liver Failure

Virtual high-throughput screening: Potential inhibitors targeting aminopeptidase N (CD13) and PIKfyve for SARS-CoV-2. (PubMed, Open Life Sci) - "The results showed that dihydroergotamine, Saquinavir, Olysio, Raltegravir, and Ecteinascidin had inhibitory effects on CD13. Dihydroergotamine, Sitagliptin, Olysio, Grazoprevir, and Saquinavir could inhibit PIKfyve...Hydrogen bonds and van der Waals forces were formed with target proteins. At the same time, the seven compounds showed good binding free energy after binding to the target proteins, providing potential drug candidates for the treatment and prevention of SARS-CoV-2 and SARS-CoV-2 variants."

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

Sustained virologic response outcomes in patient with hemodialysis - hepatitis c receiving treatment with direct-acting antivirals agents (EASL-ILC 2023) - "From 90 patients naïve HCV on hemodialysis, 75 of them had received DAAs with regimen Sofosbuvir/Simeprevir, Sofosbuvir/Daclastavir, Sofosbuvir/Ribavirin, and Elbastavir/Grazoprevir. DAA-mediated SVR12 in HCV dialysis patients resulted in high rate SVR12 >90% and similar rate in all CP class, cirrhosis status with improvement of hepatic fibrosis and kidney function especially on sofosbufir/daclastavir regimen."

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

Development of an assay pipeline for the discovery of novel small molecule inhibitors of human glutathione peroxidases GPX1 and GPX4. (PubMed, Redox Biol) - "Additionally, every GPX1 inhibitor identified (including omapatrilat, tenatoprazole, cefoxitin and ceftibuten) showed similar inhibitory activity against GPX2...Compounds only inhibiting GPX4 included pranlukast sodium hydrate, lusutrombopag, brilanestrant, simeprevir, grazoprevir (MK-5172), paritaprevir, navitoclax, venetoclax and VU0661013. Two compounds (metamizole sodium and isoniazid sodium methanesulfate) inhibited all three GPXs but not TXNRD1, while 2,3-dimercaptopropanesulfonate, PI4KIII beta inhibitor 3, SCE-2174 and cefotetan sodium inhibited all tested selenoproteins (but not GR)...With this approach, we could indeed identify novel GPX1/GPX2- or GPX4-specific inhibitors, thus presenting a validated pipeline for future identification of specific selenoprotein-targeting agents. Our study also identified GPX1/GPX2, GPX4 and/or TXNRD1 as targets for several previously developed pharmacologically active compounds."

Journal • Oncology • GPX1 • GPX2 • GPX4

Molecular insights into the in silico discovery of corilagin from Terminalia chebula as a potential dual inhibitor of SARS-CoV-2 structural proteins. (PubMed, J Biomol Struct Dyn) - "Even FDA-approved drugs like dexamethasone and grazoprevir are not able to curb the viral progression inside the host and are reported with adverse effects on body metabolism. This is also confirmed by the changes in the protein conformations, evaluated using free energy landscapes. Outcomes from this investigation identify corilagin as the lead potential dual inhibitor of S and N proteins of SARS-CoV-2, which could be taken for biological studies in near future.Communicated by Ramaswamy H. Sarma."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Improving Dissolution Performance and Drug Loading of Amorphous Dispersions Through a Hierarchical Particle Approach. (PubMed, J Pharm Sci) - "Grazoprevir exposure in dogs was higher when the hierarchical cPAD was dosed, with ∼1.8 fold increase in AUC compared to the binary cPAD. These observations highlight the important interplay between processing conditions and ASD performance in the context of cPAD particles and illustrate a hierarchical particle design as a successful approach to alter ASD surface chemistry to improve dissolution performance."

Journal

A degron system targeting endogenous PD-1 inhibits the growth of tumor cells in mice. (PubMed, NAR Cancer) - "SMASh degron-tagged PD-1-mCherry in Jurkat cells and CD3 splenocytes were degraded by the NS3/4A protease inhibitors, asunaprevir (ASV) or grazoprevir (GRV). This is the first study to use a degron tag targeting an endogenous mouse protein in vivo. Our experimental system using the SMASh degron may be employed for treating diseases and characterizing the cellular functions of essential proteins."

Journal • Preclinical • Colon Cancer • Colorectal Adenocarcinoma • Gastrointestinal Cancer • Oncology • Targeted Protein Degradation • Transplantation • PD-1

Multi-Arming and Regulator Dial Gene Circuits to Address Key Disease Challenges in HCC (ASGCT 2022) - " SENTI-301 is an allogeneic natural killer (NK) cell engineered to express a GPC3 CAR, a calibrated release IL-15 (crIL-15), and a Regulator Dial gene circuit containing a synthetic transcription factor (TF), and a Regulator Dial TF-responsive element to control expression of crIL-12 by grazoprevir (GRZ) an FDA-approved small molecule, for precise and tunable control of dose, timing and duration of crIL-12 expression, allowing SENTI-301 to overcome the challenging TME in HCC while avoiding safety issues... The combination of a multi-armed CAR-NK cell-based therapy with a Regulator Dial gene circuit is designed to address existing challenges of current immunotherapies for solid tumors. To our knowledge, SENTI-301 represents the first product candidate providing a potentially improved and more efficacious treatment option for HCC patients."

IO biomarker • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • GPC3 • IL12A • IL15