- |||||||||| grazoprevir (MK-5172) / Merck (MSD)
Drug-Controlled Anti-PD-1 CAR T-Cells to Target the Replication-Competent Reservoir in Tfh Cells (Poster hall) - Mar 16, 2024 - Abstract #CROI2024CROI_989;
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 determine their contribution to the latent reservoir.
- |||||||||| grazoprevir (MK-5172) / Merck (MSD)
Journal: Engineered poly(A)-surrogates for translational regulation and therapeutic biocomputation in mammalian cells. (Pubmed Central) - Jan 8, 2024
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: Development of an assay pipeline for the discovery of novel small molecule inhibitors of human glutathione peroxidases GPX1 and GPX4. (Pubmed Central) - Jun 7, 2023
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.
- |||||||||| grazoprevir (MK-5172) / Merck (MSD)
Journal: Improving Dissolution Performance and Drug Loading of Amorphous Dispersions Through a Hierarchical Particle Approach. (Pubmed Central) - Dec 28, 2022
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.
- |||||||||| grazoprevir (MK-5172) / Merck (MSD), Sunvepra (asunaprevir) / BMS
Preclinical, Journal: A degron system targeting endogenous PD-1 inhibits the growth of tumor cells in mice. (Pubmed Central) - Jun 24, 2022
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.
- |||||||||| Preclinical, Journal: In Vitro Assessment of Transporter Mediated Perpetrator DDIs for Several Hepatitis C Virus Direct-Acting Antiviral Drugs and Prediction of DDIs with Statins Using Static Models. (Pubmed Central) - May 6, 2022
Inhibitory effects of asunaprevir, daclatasvir, grazoprevir, paritaprevir, simeprevir, and voxilaprevir, direct-acting antiviral (DAA) drugs for the treatment of chronic hepatitis C virus (HCV) infection, were evaluated in vitro against a range of clinically important drug transporters...Furthermore, we refined and developed static models to predict complex DDIs with several statins (pitavastatin, rosuvastatin, atorvastatin, and pravastatin) by mechanistically assessing differential inhibitory effects of perpetrator drugs on multiple transporters, such as organic anion transporting polypeptides (OATP1B), breast cancer resistance protein (BCRP), multidrug resistance protein 2 (MRP2), organic anion transporter 3 (OAT3), and cytochrome P450 CYP3A enzyme, as they are known to contribute to absorption, distribution, metabolism and excretion (ADME) of above statins...Our studies suggest that mechanistic static model is a promising and useful tool to provide more accurate prediction of the risk and magnitude of DDIs with statins in early drug development and may help to improve the management of clinical DDIs for HCV drugs to ensure effective and safe HCV therapy. GRAPHICAL ABSTRACT.
- |||||||||| grazoprevir (MK-5172) / Merck (MSD)
Multi-Arming and Regulator Dial Gene Circuits to Address Key Disease Challenges in HCC (Poster Board Number: M-233; Hall D) - Apr 20, 2022 - Abstract #ASGCT2022ASGCT_733;
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.
- |||||||||| grazoprevir (MK-5172) / Merck (MSD), Daklinza (daclatasvir) / BMS, Sovaldi (sofosbuvir) / Gilead
Review, Journal: Antivirals against HCV infection: the story thus far. (Pubmed Central) - Apr 1, 2022
Despite these milestones, the WHO global target of eliminating hepatitis C as a public health problem by 2030 seems uncertain. In this review, we provide a concise account of the evolution and advancements in the development of anti-HCV regimens.
- |||||||||| Preclinical, Journal: Evaluation of the Potency of Anti-HIV and Anti-HCV Drugs to Inhibit P-Glycoprotein Mediated Efflux of Digoxin in Caco-2 Cell Line and Human Precision-Cut Intestinal Slices. (Pubmed Central) - Feb 27, 2022
However, abacavir, dolutegravir, maraviroc, sofosbuvir, tenofovir disoproxil fumarate, and zidovudine had no inhibitory effect...More inhibitors were identified when using digoxin as the ABCB1 probe substrate than when using rhodamine123. However, both approaches had limitations, indicating that inhibitory potency should be tested with at least these two ABCB1 probes.
- |||||||||| grazoprevir (MK-5172) / Merck (MSD), glecaprevir (ABT-493) / AbbVie
Journal: Amino acid and peptide-based antiviral agents. (Pubmed Central) - Feb 24, 2022
grazoprevir, glecaprevir), and HCV NS5A protein inhibitors have contributed to a significant decrease in mortality from AIDS and hepatitis...Herein we present a concise review of antiviral agents whose structures are based on amino acids of both natural and unnatural origin. A special attention is paid to the synthetic aspects of non-proteinogenic amino acid components of those agents.
- |||||||||| grazoprevir (MK-5172) / Merck (MSD), elbasvir (MK-8742) / Merck (MSD)
Invention of grazoprevir: A macrocyclic HCV NS3/4a protease inhibitor for the treatment of the hepatitis C virus infection (Room: Thomas Murphy Ballroom Sections 3 & 4) - Aug 13, 2021 - Abstract #ACSFall2021ACS_Fall_9247;
The utilization of a molecular modeling-based strategy to identify the novel P2-P4 macrocyclic series along with a flexible and reliable synthetic route which enabled rapid synthesis of diverse analogs, was key to the ultimate successful invention of grazoprevir. While the key steps leading to the design of grazoprevir will be the focus, this presentation will also highlight the development of a scalable synthetic route and several of the key clinical studies which demonstrated the robust activity of the fixed-dose combination ZEPATIER.
- |||||||||| grazoprevir (MK-5172) / Merck (MSD), velpatasvir (GS-5816) / Gilead
Journal: SAR study of bisamides as cyclophilin a inhibitors for the development of host-targeting therapy for hepatitis C virus infection. (Pubmed Central) - Jun 22, 2021
Especially inhibitors of NS3/4A protease and NS5A, such as grazoprevir and velpatasvir, have a low barrier to resistant mutations...Surface plasmon resonance experiments revealed that 7c directly binds to CypA. All these studies indicated that the derivative 7c is a potent CypA inhibitor, which can be used as a host-targeted agent in combination with other antiviral agents for anti-HCV treatment.
- |||||||||| grazoprevir (MK-5172) / Merck (MSD), Noxafil (posaconazole) / Merck (MSD)
Journal: Repurposing potential of posaconazole and grazoprevir as inhibitors of SARS-CoV-2 helicase. (Pubmed Central) - May 29, 2021
Since the amino acids are conserved among the human coronaviruses, the virus is unlikely to develop resistance mutations against these drugs. Since these drugs are already in use, they may be immediately repurposed for SARS-CoV-2 therapy.
- |||||||||| Clinical, Review, Journal: Direct-Acting Antivirals interactions with opioids, alcohol or illicit drugs in HCV-infected patients. (Pubmed Central) - Mar 24, 2021
Based on pharmacological considerations, neither efficacy loss, nor adverse drug event associated with detrimental interaction are expected with opioids, stimulants, cannabinoids, and ethanol. In summary, our literature review shows that the interaction potential of DAA with most opioids and illicit drugs is limited and should not be a hurdle to the initiate DAA.
- |||||||||| grazoprevir (MK-5172) / Merck (MSD), glecaprevir (ABT-493) / AbbVie
Journal: Molecular and structural mechanism of pan-genotypic HCV NS3/4A protease inhibition by glecaprevir. (Pubmed Central) - Feb 10, 2021
Our crystal structures reveal molecular mechanisms behind pan-genotypic activity of GLE, including potency loss due to RASs at D168. Our structures permit for the first time analysis of changes due to polymorphisms among genotypes, providing insights into design principles that can aid future drug development and potentially can be extended to other proteins.
- |||||||||| Journal: Raltegravir, Indinavir, Tipranavir, Dolutegravir, and Etravirine against main protease and RNA-dependent RNA polymerase of SARS-CoV-2: A molecular docking and drug repurposing approach. (Pubmed Central) - Dec 18, 2020
Future clinical studies examining these drugs might come to conclude, which can be more useful to inhibit COVID-19 progression. This study suggests that the screened small molecule antiviral drugs Raltegravir, Indinavir, Tipranavir, Dolutegravir, and Etravirine could serve as potential drugs for the treatment of COVID-19 with further validation studies.
- |||||||||| grazoprevir (MK-5172) / Merck (MSD)
Journal: Avoiding Drug Resistance by Substrate Envelope-Guided Design: Toward Potent and Robust HCV NS3/4A Protease Inhibitors. (Pubmed Central) - Dec 17, 2020
Our design strategy achieved better resistance profiles over both the FDA-approved NS3/4A PI grazoprevir and the parent compound against the clinically relevant D168A substitution...Optimally filling the S4 pocket is critical to avoid resistance and improve potency. Our results provide drug design strategies to avoid resistance that are applicable to other quickly evolving viral drug targets.
- |||||||||| grazoprevir (MK-5172) / Merck (MSD), doxycycline / Generic mfg., Pierre Fabre
PK/PD data, Journal: Identification of potential inhibitors against SARS-CoV-2 by targeting proteins responsible for envelope formation and virion assembly using docking based virtual screening, and pharmacokinetics approaches. (Pubmed Central) - Oct 4, 2020
All these compounds not only showed excellent pharmacokinetic properties, absorption, metabolism, minimal toxicity and bioavailability but were also remain stabilized at the active site of proteins during the MD simulation. Thus, the identified lead compounds may act as potential molecules for the development of effective drugs against SARS-CoV-2 by inhibiting the envelope formation, virion assembly and viral pathogenesis.
- |||||||||| Journal: HCV genotype 1-6 NS3 residue 80 substitutions impact protease inhibitor activity and promote viral escape. (Pubmed Central) - Sep 24, 2020
Thus, the identified lead compounds may act as potential molecules for the development of effective drugs against SARS-CoV-2 by inhibiting the envelope formation, virion assembly and viral pathogenesis. Position-80-substitutions had relatively low fitness cost and the potential to promote HCV escape from clinically relevant PIs in vitro, despite minor impact in classical short-term resistance assays.
- |||||||||| grazoprevir (MK-5172) / Merck (MSD)
Journal: Possibilities And Limiting Factors For Use Of Dissolution As A Quality Control Tool To Detect Presence Of Crystallinity For Amorphous Solid Dispersions: An Experimental And Modeling Investigation. (Pubmed Central) - Aug 23, 2020
In this article, experiments on tablets containing a model compound, grazoprevir, were conducted to explore how media selection for a quality control dissolution method can influence the sensitivity for the dissolution method toward drug crystallinity detection in an amorphous solid dispersion formulation...Additionally, it is demonstrated that the method sensitivity and accuracy might be reduced if the crystalline particles are sufficiently small with respect to the solid dispersion particles. To further demonstrate the limits of the dissolution method, a dissolution model was also explored to simulate and predict the sensitivity of the dissolution response towards crystallinity based on solubility in the media and particle size of the crystals.
- |||||||||| Journal: Features of resistance-associated substitutions after failure of multiple direct-acting antiviral regimens for hepatitis C. (Pubmed Central) - Aug 22, 2020
R30H and L31-RAS in NS5A were frequently detected after failure of regimens including daclatasvir...S282T RAS in NS5B was detected in 3.9% of ledipasvir/sofosbuvir failures...We investigated RASs after failure of various treatments for chronic hepatitis C, and found that more complicated RASs accumulated in the viral genome with successive failed treatments. The highly resistant P32del RAS at NS5A region was uniquely found in patients for whom DAA treatments had failed, and was linked to the presence and absence of specific RASs.
- |||||||||| grazoprevir (MK-5172) / Merck (MSD)
Journal: Hemoprotein-catalyzed cyclopropanation en route to the chiral cyclopropanol fragment of grazoprevir. (Pubmed Central) - Feb 7, 2020
Here we describe hemoprotein cyclopropanation catalysts derived from thermophilic bacterial globins that react with diazoacetone and an unactivated olefin substrate to furnish a cyclopropyl ketone, a previously unreported reaction for enzyme catalysts. We further demonstrate that the resulting cyclopropyl ketone can be converted to a key cyclopropanol intermediate that occurs en route to the anti-hepatitis C drug grazoprevir.
- |||||||||| Ruzasvir (MK-8408) / Merck (MSD), grazoprevir (MK-5172) / Merck (MSD)
Preclinical, Journal: In Vitro Antiviral Profile of Ruzasvir: A Potent and Pan-genotype Inhibitor of HCV NS5A. (Pubmed Central) - Oct 10, 2019
The interaction of ruzasvir with NS3/4A protease inhibitor (grazoprevir) and NS5B polymerase (uprifosbuvir) pro-drug was additive to synergistic with no evidence of antagonism or cytotoxicity. The antiviral profile of ruzasvir supported its further evaluation in human trials in combination with grazoprevir and uprifosbuvir.
- |||||||||| Journal: Direct-Acting Antivirals to Prevent Vertical Transmission of Viral Hepatitis C: When Is the Optimal Time to Treat? (Pubmed Central) - Sep 26, 2019
The antiviral profile of ruzasvir supported its further evaluation in human trials in combination with grazoprevir and uprifosbuvir. Data to determine the best treatment point along the pregnancy-pediatric continuum are limited; however, given the lack of human data for use of DAAs during pregnancy, low rate of VT, high rate of spontaneous pediatric clearance, and recent approval of DAAs for pediatric patients, treatment of chronically infected children seems to be the optimal strategy currently.
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