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

Deep learning-based prediction of drug-target interactions between antiviral drugs and SARS-CoV-2 proteins using an image-based representation approach. (PubMed, Comput Biol Chem) - "Results consistently identified five antivirals - MK-5172 (Grazoprevir), Simeprevir, Lopinavir, Etravirine, and Atazanavir - as top-ranked candidates across all targets. Comparative analysis with the MT-DTI model demonstrated competitive and, in several cases, superior ranking performance despite a simpler architecture. Importantly, these predictions are supported by independent experimental and clinical evidence, highlighting the potential of image-based representations as a computationally efficient and biologically meaningful approach for drug-target interaction prediction and drug repurposing."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Systemic grazoprevir-inducible AAV vectors for gene therapy (ASGCT 2026) - "Notably, GZV-regulated systems displayed no observable wash-out during a one-week period of no inducer, suggesting a prolonged synTF half-life and raising important questions for future pharmacokinetic studies. Conclusion This work demonstrates the potential for precise, adjustable transgene expression control in liver-directed gene therapy applications, enhancing therapeutic versatility across clinical applications."

Gene therapy • Gene Therapies • Hepatitis C • Hepatology • Infectious Disease • Inflammation

Repurposing antiviral drugs targeting RNA viruses: A focus on the fusion protein of human metapneumovirus. (PubMed, North Clin Istanb) - "This study provides compelling in silico evidence that drug repurposing of clinically approved antiviral agents may accelerate the development of effective HMPV-specific therapies. By targeting the highly conserved and functionally critical HMPV F protein, the identified candidate compounds offer strong translational potential and justify prioritization for experimental validation and preclinical investigation. Collectively, these results contribute to filling a critical therapeutic gap and support drug repurposing as a viable and time-efficient strategy to address emerging and neglected viral respiratory infections."

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

STRAIGHT-IN Dual: a platform for dual single-copy integrations of DNA payloads and gene circuits into human induced pluripotent stem cells. (PubMed, Nat Biomed Eng) - "We also incorporate a grazoprevir-inducible synthetic gene switch that complements tetracycline-inducible control, providing tunable and temporally controlled expression of different transcription factors within the same cell. STRAIGHT-IN Dual generates homogeneous engineered hiPSC populations, accelerating synthetic biology design-build-test cycles in stem cells and enabling controlled comparisons of circuit performances."

Journal

High-throughput automated molecular replacement for small-molecule MicroED data. (PubMed, IUCrJ) - "The method was validated against three similar macrocycles with known structures (paritaprevir-α, paritaprevir-β and grazoprevir) at varying data resolution limits (1.0, 1.2, 1.4, 1.5, 1.6, 1.8 and 2.0 Å). At all these resolutions for all three structures, the developed workflow was successful and produced solutions with R factors and RMSD values within acceptable limits of the ab initio solved structure."

Journal

Conformational Trajectory of the Molecular Chameleon Grazoprevir from Formulation to Target-Bound. (PubMed, Chemistry) - "In apolar environment, mimicking the cell membrane, intramolecular hydrogen bonding promoted the formation of compact conformations with reduced radii of gyration and solvent accessible 3D polar surface area, likely facilitating cell permeability. This work presents a comprehensive conformational trajectory of a macrocyclic chameleon and provides potential insights into understanding and characterizing cell permeability and chameleonicity of similar bRo5 therapeutics."

Journal

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