GS-441524 / Copycat Sci - LARVOL DELTA

Practical approach to development of GS-445124-loaded PLGA nanoparticles for the long-term treatment of feline infectious peritonitis caused by feline coronavirus infection. (PubMed, Int J Pharm) - "When GS-PLGA NP was injected at 22 mg/kg in cats, higher systemic exposure can be expected compared to injecting GS-441524 at 4 mg/kg for one week (relative bioavailability, 152 %). As well as GS-PLGA NP showed lower toxicity, improved cellular uptake, and enhanced antiviral efficacy against FCoV compared to the pure GS-441524."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

REMDESIVIR INDUCED HEART BLOCK - Shazia Pathan (ACC 2025) - "This case presents a life-threatening drug reaction, advocating telemetry monitoring with Remdesivir. The patient being asymptomatic, while in complete A-V dissociation, suggests that this may be more common than we have clinically recognized. The half-life of Remdesivir's active metabolite, GS-441524, is ~27 hours."

Cardiovascular • Infectious Disease • Metabolic Disorders • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases

Pharmacokinetics of GS-441524 following intravenous remdesivir in six cats and results of therapeutic drug monitoring during treatment of feline infectious peritonitis: 22 cases (2021-2024). (PubMed, J Small Anim Pract) - "This study supports the use of RDV and GS-441524 for FIP treatment and suggests that population pharmacokinetic modelling is required to better explore the utility of therapeutic drug monitoring of GS-441524."

Journal • PK/PD data

The oral drug obeldesivir protects nonhuman primates against lethal Ebola virus infection. (PubMed, Sci Adv) - "Obeldesivir (ODV; GS-5245) is an orally administered ester prodrug of the parent nucleoside GS-441524 that has broad spectrum antiviral activity inhibiting viral RNA-dependent RNA polymerases. For outbreak response, oral antivirals might present substantial advantages over now approved intravenous drugs, such as easy supply, storage, distribution, and administration. Furthermore, these results support the potential of ODV as an oral postexposure prophylaxis with broad spectrum activity across filoviruses."

Journal • Ebola Virus Disease • Infectious Disease • Inflammation

The Nucleoside Analog GS-441524 Effectively Attenuates the In Vitro Replication of Multiple Lineages of Circulating Canine Distemper Viruses Isolated from Wild North American Carnivores. (PubMed, Viruses) - "Six antiviral compounds were selected after preliminary experiments that excluded ribavirin, hesperidin and rutin: a protease inhibitor (nirmatrelvir), a polymerase inhibitor (favipiravir) and four nucleoside analogs (remdesivir, GS-441524, EIDD2801 and EIDD1931). Several of the nucleoside analogs have been safely used previously in carnivore species for the treatment of other viral diseases, suggesting that they may be promising candidates for the treatment of canine distemper in dogs. Our results emphasize the need to consider different viral lineages in the screening of antiviral compounds."

Journal • Preclinical • Infectious Disease

The Combination of GS-441524 (Remdesivir) and Ribavirin Results in a Potent Antiviral Effect Against Human Parainfluenza Virus 3 Infection in Human Airway Epithelial Cell Cultures and in a Mouse Infection Model. (PubMed, Viruses) - "Moreover, several mice in the single-treatment groups exhibited severe lung pathology. These findings may warrant exploring this combination in patients with severe HPIV-3 infections and possibly also against infections with other viruses that are susceptible in vitro to these two drugs."

Journal • Preclinical • Infectious Disease • Pneumonia • Respiratory Diseases

Remdesivir is active in vitro against tick-borne encephalitis virus and selects for resistance mutations in the viral RNA-dependent RNA polymerase. (PubMed, Infect Dis (Lond)) - "TBEV was cultured in A549 cells, and the inhibitory effects of RDV (GS-5734), its parent nucleotide GS-441524, and SOF (GS-7977) were assessed. RDV exhibits potent in vitro antiviral activity against TBEV via specific targeting of the viral RdRp as confirmed by the emergence of resistance-associated double NS5 substitutions in vitro in the presence of RDV. While the potential in vivo implications of the observed RDV resistance remain to be determined, these in vitro data support further assessment of RDV for the treatment of TBEV infection."

Journal • Preclinical • CNS Disorders • Infectious Disease

GS-441524 for COVID-19 SAD, FE, and MAD Study in Healthy Subjects (clinicaltrials.gov) - P1 | N=0 | Withdrawn | Sponsor: National Center for Advancing Translational Sciences (NCATS) | N=70 ➔ 0 | Not yet recruiting ➔ Withdrawn

Enrollment change • Trial withdrawal • Infectious Disease • Novel Coronavirus Disease

Pharmacokinetics of SARS-CoV-2 RNA Polymerase Inhibitor Remdesivir in Participants With Moderate and Severe Hepatic Impairment. (PubMed, Clin Transl Sci) - "The prodrug, remdesivir, undergoes metabolic activation inside the cell to form the intracellular active metabolite (GS-443902) along with two plasma metabolites (GS-704277 and GS-441524). Remdesivir was generally safe and well tolerated in hepatically impaired individuals, and the modest exposure increases of remdesivir and its metabolites were not associated with adverse events. Based on these findings, no dose adjustment of remdesivir is recommended for patients with mild, moderate, or severe hepatic impairment."

Clinical • Journal • PK/PD data • Hepatology • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Clinical Evaluation of Drug-Drug Interactions with Obeldesivir, an Orally Administered Antiviral Agent. (PubMed, Clin Pharmacol Ther) - "When obeldesivir was tested as a precipitant, pharmacokinetic parameter point estimates for midazolam (CYP3A4 inhibition/induction), caffeine (CYP1A2 inhibition), and metformin (organic cation transporter 1 inhibition) exposures were within 80-125% no-effect bounds representing the interval within which a systemic exposure change does not warrant clinical action based on EMA/FDA guidance. Dabigatran (P-glycoprotein substrate) and pitavastatin (organic anion transporting polypeptide 1B1/1B3 substrate) exposures decreased by approximately 25% and 30%, respectively, with obeldesivir coadministration; these were considered not clinically relevant, as these exposure changes are not associated with dose changes or precautions in the US prescribing information for these drugs. When obeldesivir was evaluated as an object, exposures of GS-441524, the parent nucleoside monophosphate metabolite of obeldesivir, were within the 80-125% no-effect bounds for ritonavir (P-glycoprotein..."

Journal • Breast Cancer • Infectious Disease • Novel Coronavirus Disease • Oncology • Respiratory Diseases • Solid Tumor • CYP1A2 • SLC22A1

Cepharanthine: A promising natural compound against feline infectious peritonitis virus infection and associated inflammation. (PubMed, Virology) - "The combination of CEP and GS-441524 exhibited synergistic antiviral effects against FIPV infection. Our findings highlight the therapeutic potential of CEP for treatment of FIP."

Journal • Infectious Disease • Inflammation

Predictive factors associated with short-term mortality in cats with feline infectious peritonitis treated with remdesivir or GS-441524 or both. (PubMed, J Vet Intern Med) - "Increased plasma LDH activity might be useful for predicting short-term mortality, guiding monitoring, and establishing prognosis in cats with FIP."

Biomarker • Clinical • Journal • Infectious Disease • Novel Coronavirus Disease

Clinical Pharmacokinetics and Safety of Remdesivir in Phase I Participants with Varying Degrees of Renal Impairment. (PubMed, Clin Pharmacokinet) - "Observed pharmacokinetics for remdesivir and its metabolites in participants with renal impairment aligned with expected changes based on known routes of elimination. Remdesivir was generally safe and well tolerated in participants with renal impairment, and no new safety concerns were identified. These results, along with those from the phase III study in patients with COVID-19 with severely reduced kidney function, support the use of remdesivir in patients with any degree of renal impairment with no dose adjustments."

Journal • P1 data • PK/PD data • Chronic Kidney Disease • Infectious Disease • Novel Coronavirus Disease • Renal Disease

Multidrug Combinations against SARS-CoV-2 Using GS-441524 or Ivermectin with Molnupiravir and/or Nirmatrelvir in Reconstituted Human Nasal Airway Epithelia. (PubMed, Pharmaceutics) - "Conclusions. In general, we observed that the addition of a third compound is not beneficial for antiviral activity, while various double combinations exhibit increased antiviral activity over single treatment."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Open label clinical trial of orally administered molnupiravir as a first-line treatment for naturally occurring effusive feline infectious peritonitis. (PubMed, J Vet Intern Med) - "Molnupiravir is an effective antiviral treatment for effusive FIP."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Exploration of isatin-based inhibitors of SARS-CoV-2 Nsp15 endoribonuclease. (PubMed, Eur J Med Chem) - "A straightforward solvent free and green, microwave-assisted synthetic process was established to achieve the development of the different target compounds. The best compound exhibited inhibitory activity in enzymatic EndoU assays, and reduced the SARS-CoV-2 viral RNA load by almost 68,000-fold in the low micromolar range similarly to the established antiviral agent GS-441524."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Oral pharmacokinetics and efficacy of oral phospholipid remdesivir nucleoside prodrugs against SARS-CoV-2 in mice. (PubMed, Antimicrob Agents Chemother) - "We previously synthesized 1-O-octadecyl-2-O-benzyl-sn-glyceryl-P-RVn (ODBG-P-RVn, V2043), a phospholipid prodrug of GS-441524 (remdesivir nucleoside, RVn), and demonstrated its in vivo efficacy in a SARS-CoV-2 mouse model. On a molar basis, V2043 and V2067 are substantially more active than obeldesivir/GS-5245 and molnupiravir in vivo. Together, these data support the continued development of phospholipid RVn prodrugs for the treatment of SARS-CoV-2 and other RNA viruses of clinical concern."

Journal • PK/PD data • Preclinical • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

A robust mouse model of HPIV-3 infection and efficacy of GS-441524 against virus-induced lung pathology. (PubMed, Nat Commun) - "Thus, AG129 mice serve as a robust preclinical model for developing therapeutic and prophylactic strategies against HPIV-3. We suggest further investigation of GS-441524 and its prodrug forms to treat HPIV-3 infection in humans."

Journal • Preclinical • Infectious Disease • Respiratory Diseases • IFNA1 • IFNG

The triple combination of Remdesivir (GS-441524), Molnupiravir and Ribavirin is highly efficient in inhibiting coronavirus replication in human nasal airway epithelial cell cultures and in a hamster infection model. (PubMed, Antiviral Res) - "Yet, in the lungs of all hamsters that received triple prophylactic therapy (but not in those that received the respective double combinations) no infectious virus was detectable. Our findings indicate that co-administration of approved drugs for the treatment of coronavirus infections should be further explored but also against other families of viruses with epidemic and pandemic potential for which no effective antiviral treatment is available."

Journal • Preclinical • Human Immunodeficiency Virus • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Clinical pharmacodynamics of obeldesivir versus remdesivir. (PubMed, Antimicrob Agents Chemother) - No abstract available

Journal • PK/PD data

GS-441524 and molnupiravir are similarly effective for the treatment of cats with feline infectious peritonitis. (PubMed, Front Vet Sci) - "Adverse events, such as primarily hepatic function abnormalities, were transient and resolved without specific intervention. Our data indicate that GS-441524 and molnupiravir show similar effects and safety in cats with FIP."

Journal • CNS Disorders • Epilepsy • Infectious Disease • Novel Coronavirus Disease

Short Treatment of 42 Days with Oral GS-441524 Results in Equal Efficacy as the Recommended 84-Day Treatment in Cats Suffering from Feline Infectious Peritonitis with Effusion-A Prospective Randomized Controlled Study. (PubMed, Viruses) - "All cats that completed the short treatment course successfully were still in complete remission on day 168. Therefore, a shorter treatment duration of 42 days GS-441524 15 mg/kg can be considered equally effective."

Journal • Infectious Disease • Novel Coronavirus Disease

Regioselective Homolytic C2-H Borylation of Unprotected Adenosine and Adenine Derivatives via Minisci Reaction. (PubMed, J Am Chem Soc) - "This protocol proved effective for the late-stage borylation of some important biomolecules as well as a few antiviral and antitumor drug molecules, such as AMP, cAMP, Vidarabine, Cordycepin, Tenofovir, Adefovir, GS-441524, etc. Theoretical calculations shed light on the site selectivity, revealing that the free energy barriers for the C2-Minisci addition are further lowered through the chelation of additive Mg2+ to N3 and furyl oxygen. This phenomenon has been confirmed by an IGMH analysis. Preliminary antitumor evaluation, derivation of the C2-borylated adenosine to other analogues with high-value functionalities, along with the CuAAC click reactions, suggest the potential application of this methodology in drug molecular optimization studies and chemical biology."

Journal • Oncology

Assessment of remdesivir and its nucleoside metabolite in beagle dogs and healthy humans by liquid chromatography coupled with triple quadrupole mass spectrometry. (PubMed, Biomed Chromatogr) - "The aim of this study was to assess the pharmacokinetics of the existing remdesivir intravenous formulation (100 mg dose) against the newly developed oral formulation (20 mg dose) for remdesivir and its active nucleoside metabolite (GS-441524) in beagle dogs followed by healthy human volunteers. The recovery was >90% in beagle dog and human plasma. These methods were successfully used to determine the pharmacokinetic parameters of the intravenous injection and subcutaneous tablets dosage forms in beagle dogs and healthy humans."

Journal

Novel immunomodulatory properties of adenosine analogs promote their antiviral activity against SARS-CoV-2. (PubMed, EMBO Rep) - "In the case of remdesivir, we here show that these properties are due to its metabolite, GS-441524, acting as an Adenosine A2A Receptor antagonist. Our findings support a new rationale for the design of next-generation antiviral agents with dual - immunomodulatory and intrinsic - antiviral properties. These compounds could represent game-changing therapies to control emerging viral diseases and future pandemics."

Immunomodulating • Journal • Infectious Disease • Novel Coronavirus Disease • Oncology • Respiratory Diseases • ADORA2A