GS-441524 / Copycat Sci - LARVOL DELTA

Remdesivir Maintains Antiviral Potency Against Clinically Relevant SARS-CoV-2 Nsp12 Substitutions. (PubMed, Antiviral Res) - "Using a recombinant infectious SARS-CoV-2 reporter virus, we compared susceptibility of these nsp12 substitutions to RDV and its parent nucleoside, GS-441524. Collectively, these data reinforce the high genetic barrier to RDV resistance, as reduced susceptibility is typically accompanied by substantial reductions in replication. Our findings support the continued clinical utility of RDV and highlight the complementary value of SARS-CoV-2 infectious virus and replicon systems for antiviral resistance surveillance and phenotyping."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Repurposing GS-441524 to inhibit biofilm formation and virulence of Bacillus cereus. (PubMed, Biofouling) - "In a Galleria mellonella model, GS-441524 enhanced survival upon B. cereus challenge. These findings demonstrate that GS-441524 disrupts QS and virulence, offering a promising strategy to control B. cereus."

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Development of GS-441524 derivatives as potent SARS-CoV-2 Mac1 inhibitors via a direct-to-biology approach. (PubMed, Eur J Med Chem) - "This approach leverages efficient amide-coupling reaction and the mix-and-read fluorescence polarization (FP) assays where reaction mixtures could be screened directly without purification. Cocrystal structure of a selected derivative (12p) binding to SARS-CoV-2 Mac1 revealed the binding mode, which will guide future drug development against viral macrodomains."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Structural determinants of Mac1 inhibition: Lessons from ligand binding patterns. (PubMed, Int J Biol Macromol) - "In this study we used volume-based metadynamics simulations to investigate the binding mechanisms of ADP-ribose and two Mac1 inhibitors: the adenine-analogue GS-441524 and the non-adenine-analogue S09...Within this loop, Leu126, part of the virus-specific P-L-L-S motif, serves as a key anchoring residue for potent inhibitors. Collectively, these findings suggest that targeting both the oxyanion hole and Leu126 may enhance both the specificity and affinity of next-generation Mac1 inhibitors."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

EXPRESS: Renal Health in Cats with Feline Infectious Peritonitis treated with GS-441524: Baseline Findings and Longitudinal Effects. (PubMed, J Feline Med Surg) - "A small subset of cats met criteria compatible with potential renal dysfunction during the study. Whether these findings reflect delayed FIP-related renal insults or adverse antiviral effects remains unknown but indicate that treatment should not be extended unnecessarily."

Journal • Infectious Disease • Inflammation • Nephrology • Novel Coronavirus Disease • Renal Disease

Clinical and imaging findings after antiviral treatment in cats with presumptive neurologic feline infectious peritonitis: 9 cases (2020-2024). (PubMed, J Vet Intern Med) - "Clinical improvement is not always consistent with radiologic resolution in cats with neurologic FIP treated with antivirals. Post-treatment MRI findings, particularly persistent or worsening obstructive hydrocephalus, should be interpreted alongside clinical status rather than as a sole indicator of therapeutic response."

Journal • Retrospective data • CNS Disorders • Otorhinolaryngology • Ventriculomegaly

The Shifting Paradigm of Feline Infectious Peritonitis: New Diagnostics and Therapeutics. (PubMed, Vet Clin North Am Small Anim Pract) - "Safe and effective antiviral therapies, including GS-441524 and related compounds, have transformed FIP into a treatable disease with survival rates previously unimaginable. In parallel, advances in molecular diagnostics and immunocytochemical techniques have improved antemortem diagnostic confidence. This review explores the evolving understanding of FIP pathogenesis, diagnostic testing, and antiviral therapy, emphasizing the rapid pace of change and the implications for contemporary clinical practice."

Journal • Review • Infectious Disease • Novel Coronavirus Disease

Design, structure-based optimization and antiviral evaluation of potent inhibitors for the macrodomain Mac1 of SARS-CoV-2. (PubMed, Nat Commun) - "Based on insights from the SAR, we show β-methyl-GS-441524-diphosphate as nanomolar inhibitor that exhibits >1000-fold selectivity over human MacroD1 and MacroD2. Addition of C11-acyloxybenzyl (AB)-masking groups yields a membrane permeable, lipophilic prodrug that inhibits SARS-CoV-2 in cell culture (EC50 0.06 µM) while exhibiting low cytotoxicity (CC50 > 50 µM). Replacement of the terminal methyl phosphate with an ethyl phosphonate increases stability of the prodrug with little effect on toxicity and antiviral potency (EC50 = 0.03 µM), making it a membrane-permeable nucleotide-based prodrug against viral macrodomains."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Comparison of the permeability of RdRp inhibitors, remdesivir, molnupiravir and azvudine, in placental barrier cell models and exploration of their transport mechanisms. (PubMed, J Antimicrob Chemother) - "RDV and GS-441524 displayed low placental permeability in BeWo cells, whereas EIDD-1931 and azvudine displayed high permeability. Multiple ENTs, CNTs, OAT4, P-gp and BCRP might be involved in placental transport of RDV, GS-441524, EIDD-1931 and azvudine. These findings offer new insights into the placental transport of RdRp inhibitors during pregnancy."

Clinical • Journal • Breast Cancer • Infectious Disease • Novel Coronavirus Disease • Oncology • Respiratory Diseases • Solid Tumor • SLC29A1

Design of poly(jasmine lactone) micelles for enhanced delivery of remdesivir as a substitute for β-cyclodextrin formulations. (PubMed, J Pharm Sci) - "Remdesivir (REM), a nucleoside analogue that has been approved for SARS-CoV-2 treatment, is poorly soluble in water and is currently administered intravenously formulated with sulfobutylether-β-cyclodextrin (SBECD) to facilitate solubilization. The in vivo results also indicated an accumulation of the REM metabolite (GS-441524) in the lungs, demonstrating more targeted tissue distribution and production of active metabolites in vivo. Overall, these results provide evidence that PJL mediated micellar delivery of REM resulted in successful solubilization and delivery through a less invasive means of administration representing a promising biocompatible platform for delivering antiviral drug with improved systemic exposure."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

A novel oral prodrug (CK301) for effusive feline infectious peritonitis: An open-label study evaluating dose optimization and therapeutic efficacy. (PubMed, Vet Microbiol) - "In this open-label trial, 150 cats with naturally occurring effusive FIP were randomly assigned to receive oral CK301 tablets (Patent WO2023197791) at low, medium, or high doses; placebo; or subcutaneous GS-441524. In conclusion, medium-dose oral CK301 (12.5 mg/kg) significantly prolonged survival, highlighting its potential as a therapeutic option for effusive FIP. It offers a convenient, non-invasive alternative to injectable treatments, provided liver function is closely monitored for potential transaminase elevations."

Journal • Hepatology • Infectious Disease • Liver Failure • Novel Coronavirus Disease

The CCR2 inflammatory pathway is a target for improving severe disease and pulmonary inflammation in experimental COVID-19. (PubMed, Virulence) - "Immune-profiling by focused transcript analysis, inflammatory protein array, and multi-color flow cytometry, confirmed that clinically relevant markers of COVID-19 (IL-6, GM-CSF, neutrophils, inflammatory monocytes) were significantly elevated in lungs of mice at day 5 post-infection and that remdesivir antiviral active metabolite (GS441524) treatment significantly modified SARS-CoV2∆ viral loads and pulmonary inflammation...To address the functional relevance of the CCR2 pathway of inflammatory cell recruitment to the lungs mediating disease, mice were administered with anti-CCR2 antibody daily at the point of infection for up to 6 d. Anti-CCR2 treated mice showed significant improved welfare scores, were protected from weight loss, modified myeloid pneumonitis, and displayed significantly blunted cytokine and chemokine response in the lungs, despite not affecting pulmonary viral loads. Our data supports therapeutic benefit of modifying CCR2-dependent cell recruitment..."

Journal • Acute Respiratory Distress Syndrome • Infectious Disease • Inflammation • Novel Coronavirus Disease • Otorhinolaryngology • Pneumonia • Pulmonary Disease • Respiratory Diseases • CCL2 • CCR2 • CSF2 • IL6

Transient Myocardial Thickening in an 11-Year-Old Cat Infected With Feline Infectious Peritonitis and Treated With GS-441524. (PubMed, Case Rep Vet Med) - "To the authors' knowledge, this is one of the rare reports of transient myocardial thickening in the FIP setting, following GS-441524 treatment. Cardiac POCUS and NT-proBNP dosage in pleural effusion should systematically be performed in order to unmask congestive heart failure."

Journal • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Heart Failure • Hypertrophic Cardiomyopathy • Inflammation • Pulmonary Disease • Respiratory Diseases • TNNI3

Development of GS-441524 Derivatives as Potent SARS-CoV-2 Mac1 Inhibitors via a Direct-to-Biology Approach. (PubMed, bioRxiv) - "This approach leverages efficient amide-coupling reaction and the mix-and-read fluorescence polarization (FP) assays where reaction mixtures could be screened directly without purification. Cocrystal structure of a selected derivative ( 12p ) binding to SARS-CoV-2 Mac1 revealed the binding mode, which will guide future drug development against viral macrodomains."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Development and Physicochemical Stability of an Oral GS-441524 Suspension for Weight-Adjusted Treatment of Feline Infectious Peritonitis. (PubMed, Vet Med Sci) - "These findings support the suitability of the formulation as an extemporaneously compounded preparation under veterinary supervision. Pharmacokinetic and clinical performance were not assessed and should be addressed in future studies to further substantiate therapeutic use."

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Cellular engagement of the SARS-CoV-2 macrodomain by GS-441524 and enhanced in vitro inhibition by its diphosphorylated metabolite. (PubMed, RSC Chem Biol) - "GS-441524, the parent nucleoside of remdesivir, inhibits SARS-CoV-2 Mac1, but its active metabolite and cellular engagement were undefined. GS-441524 selectively inhibits SARS-CoV-2 Mac1 over human MacroD2, engages Mac1 in cells but not MERS-CoV Mac1, with its diphosphate metabolite being most potent."

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

Repurposing FDA-Approved Drugs as Potential Inhibitors of Feline Infectious Peritonitis Virus 3CLpro: An Integrated In Silico and In Vitro Study with Synergistic Combination Analysis. (PubMed, ACS Pharmacol Transl Sci) - "Synergy analysis with established anti-FIP agents (GC376, remdesivir, GS-441524, and molnupiravir) using SynergyFinder 3.0 revealed strong synergistic interactions: saquinavir + GC376 (mean ZIP score: 54.59), lumacaftor + GC376 (mean ZIP: 21.44), and gliquidone + remdesivir (mean ZIP: 24.13). These rational combinations enable substantial dose reduction, offering practical strategies to improve treatment accessibility, reduce costs, and minimize adverse effects. This study establishes a framework for repurposing FDA-approved drugs in FIP therapy and supports translational evaluation of these combination regimens."

FDA event • Journal • Preclinical • Infectious Disease • Novel Coronavirus Disease • IFNB1 • IL6 • TNFA

Identification of key metabolic enzymes involved in the activation of obeldesivir and remdesivir to the active triphosphate metabolite. (PubMed, Antimicrob Agents Chemother) - "Obeldesivir (GS-5245, ODV), an orally administered 5'-isobutyryl ester prodrug of GS-441524, has demonstrated anti-SARS-CoV-2 activity in preclinical and clinical settings. In contrast, both biochemical and cell-based assay data strongly support adenylate kinase 2 as the key enzyme for the phosphorylation of GS-441524-MP, while nucleoside diphosphate kinase NM23-H2, phosphoglycerate kinase, and pyruvate kinase likely all contribute to the formation of GS-441524-TP. This work leads to a deeper understanding of ODV and RDV metabolism, and suggests further studies are needed to identify the enzyme responsible for the activation of GS-441524 to its 5'-monophosphate."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • CES1

LC-MS/MS Therapeutic Drug Monitoring of GS-441524 in Serum and Various Compounded Formulations to Improve the Treatment of Feline Infectious Peritonitis. (PubMed, Animals (Basel)) - "The validated method was applied to clinical TDM in cats undergoing GS-441524 treatment for FIP, providing preliminary evidence of inter-individual pharmacokinetic variability. The compounded formulations administered to the TDM cohort were independently verified by LC-MS/MS, confirming drug content within ±15% of labelled claims and excluding pharmaceutical quality as a confounding factor in the interpretation of serum drug concentrations."

Journal • Cerebral Hemorrhage • Infectious Disease • Novel Coronavirus Disease

Optimizing drug combinations to resurrect the potency of failed antibody therapy against emerging COVID-19 variants using IDentif.AI. (PubMed, Front Digit Health) - "For instance, multiple therapeutics like Evusheld are no longer effective against current variants and therefore have their emergency use authorizations (EUA), a regulatory mechanism allowing emergency use of medical products, revoked until further notice. Similarly, sotrovimab (STV), a human neutralizing monoclonal antibody (MAB), received EUA in May 2021 and was later granted authorization for COVID-19 treatment in Singapore...IDentif.AI-pinpointed STV/EIDD-1931 and STV/GS-441524 combinations were able to interact synergistically to enhance efficacy against XBB and importantly, substantially reduce STV's in vitro EC50 (half maximal effective concentration) by up to 7-fold. This optimization platform represents a strategic approach to rapidly repurpose existing or previously failed therapeutics and subsequently restore their efficacy against a disease indication by pairing them with the correct drugs in combinations."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Epidemiological and Clinical Insights from 68 Veterinarian-Reported Cases of Feline Infectious Peritonitis During the Documented FIP Epizootic in Cyprus. (PubMed, Pathogens) - "Antiviral therapy (GS-441524 or molnupiravir) was administered in 92.2% of cases, with reported clinical improvement of 88.9%. These findings demonstrate the value of questionnaire-based surveillance in documenting outbreak-associated FIP patterns. Although individual cases were not uniformly confirmed as FCoV-23 infections, the increased proportion of neurological presentations among FIP cases reported during the epizootic period supports previous molecular evidence suggesting that neurological involvement was associated with FCoV-23 circulation."

Journal • Anorexia • Infectious Disease • Novel Coronavirus Disease

Impact of remdesivir modifications on human HINT1 binding - A structural and functional study in the remdesivir activation pathway. (PubMed, Structure) - "We report crystal structures of human HINT1 in complex with either the nucleoside GS-441524 or the monophosphate nucleoside GS-441524-MP-both metabolites of remdesivir at 1.30 Å and 1.58 Å resolution, respectively. Together with enzymatic data, these results disclose the main structural determinants governing activity, namely the steric hindrance of the phosphoramidate moiety as well as ribose modifications altering interactions with Asp43."

Journal • HINT1

Structure-activity relationship and nsp15-dependent mechanism of spirothiazolidinone derivatives with pan-coronavirus activity. (PubMed, Bioorg Chem) - "2p displayed additive antiviral effect when combined with the CoV polymerase inhibitor GS-441524, indicating mechanistic complementarity and potential for combination therapy. Collectively, these findings position our spirothiazolidinones as promising leads for further optimization toward pan-CoV drug development."

Journal • Gastroenterology • Gastrointestinal Disorder • Infectious Disease • Inflammation • Novel Coronavirus Disease • Respiratory Diseases

Pharmacokinetics, Safety, and Tolerability of Obeldesivir in Healthy Japanese and White Participants. (PubMed, Eur J Drug Metab Pharmacokinet) - "Plasma pharmacokinetic exposures of GS-441524 were higher in Japanese participants compared with white participants but were within the ranges observed in previous phase 1 studies. Differences in body weight between the populations in the study likely contributed to the increases in exposure. Obeldesivir was generally safe and well tolerated in both Japanese and white participants. These findings indicate that obeldesivir is likely to have favorable pharmacokinetic exposures and safety across different racial populations, supporting its potential use in treating multiple viral infections."

Journal • PK/PD data • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • Respiratory Syncytial Virus Infections

Update on Treatment of Feline Infectious Peritonitis: European Advisory Board on Cat Diseases (ABCD) Guidelines. (PubMed, Viruses) - "In these revised guidelines, the European Advisory Board on Cat Diseases (ABCD) presents an update on the treatment of FIP, incorporating the findings of new studies including the range of available treatments (such as GS-441524, remdesivir and molnupiravir (EIDD-2801) and its active metabolite EIDD-1931), which varies globally, as well as suggestions for monitoring and prognostic indicators...Remdesivir is primarily reserved as an injectable antiviral for severely affected cats unable to tolerate oral medication; it is usually replaced by oral medication as soon as, and when, possible. Although 84-day treatment courses have historically been used, emerging evidence suggests that shorter regimens of 42 days can be equally effective."

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