GS-6620 / Gilead - LARVOL DELTA

Differential activity of nucleotide analogs against tick-borne encephalitis and yellow fever viruses in human cell lines. (PubMed, Virology) - "Remdesivir, uprifosbuvir and sofosbuvir were the most potent drugs against TBEV and YFV in liver cells, but they had reduced activity in neural cells, whereas galidesivir retained uniform activity across cell lines and viruses. Ribavirin, valopicitabine, molnupiravir and GS-6620 exhibited only moderate antiviral activity. We found antiviral activity for drugs previously reported as inactive, demonstrating the importance of using human cell lines and comparative experimental assays when screening the activity of nucs. The relatively high antiviral activity of remdesivir, sofosbuvir and uprifosbuvir against TBEV and YFV merits further investigation in clinical studies."

Journal • Preclinical • CNS Disorders

Drug repurposing based on a quantum-inspired method versus classical fingerprinting uncovers potential antivirals against SARS-CoV-2. (PubMed, PLoS Comput Biol) - "We employed a Quadratic Unbounded Binary Optimization (QUBO) model, to search for compounds similar to Remdesivir, the first antiviral against SARS-CoV-2 approved for human use, using a quantum-inspired device...While GS-6620 was the top compound predicted by both models, the QUBO model predicted BMS-986094 as second best...While Tanimoto may be employed when performing relatively small comparisons, QUBO is also accurate and may be well suited for very complex problems where computational resources may limit the number and/or complexity of possible combinations to evaluate. Our quantum-inspired screening method can therefore be employed in future searches for novel pharmacologic inhibitors, thus providing an approach for accelerating drug deployment."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

An alternative splicing signature in human Crohn's disease. (PubMed, BMC Gastroenterol) - "Our study provided a landscape of AS events in CD, especially as the first study focused on a Chinese cohort. Our data suggest that dysregulation of AS may be a new mechanism that contributes to the pathogenesis of CD."

Journal • Crohn's disease • Gastroenterology • Immunology • Inflammatory Bowel Disease • Metabolic Disorders • IRF1 • STAT3

Bioinformatics analysis for the identification of key genes and long non-coding RNAs related to bone metastasis in breast cancer. (PubMed, Aging (Albany NY)) - "We screened differentially expressed genes and lncRNAs between normal breast and breast cancer bone metastasis samples using the GSE66206 dataset from the Gene Expression Omnibus...The role of core driver genes and lncRNAs in the network implies their biological functions in regulating bone development and remodeling. Thus, targeting the core driver genes and lncRNAs in the network may be a promising therapeutic strategy to manage bone metastasis."

Journal • Breast Cancer • Oncology • Solid Tumor

Investigational nucleoside and nucleotide polymerase inhibitors and their use in treating hepatitis C virus (Expert Opin Investig Drugs) - "Currently, mericitabine has the most robust data but its efficacy appears to be less than optimal. Other drugs such as ALS-2200 (and its diastereomer VX-135) and BMS-986094 are promising but the data in humans are too scanty to draw conclusions about their future role at this current point in time."

Review • Hepatitis C Virus

New Nucleoside Analogues for the Treatment of Hemorrhagic Fever Virus Infections. (PubMed, Chem Asian J) - "They can be considered as either (i) adenine analogues (3-deazaneplanocin A, galidesivir, GS-6620 and remdesivir) or (ii) guanine analogues containing the carboxamide entity (ribavirin, EICAR, pyrazofurin and favipiravir). Four out of the eight compounds (galidesivir, GS-6620, remdesivir and pyrazofurin) are C-nucleosides, and two of them (GS-6620, remdesivir) also contain a phosphoramidate part. The C-nucleoside and phosphoramidate (and for the adenine analogues the 1'-cyano group as well) may be considered as essential attributes for their antiviral activity."

Journal • Review

Non-proteinogenic Amino Acid Containing Nucleotide Prodrug to Improve Oral Delivery of a Hepatitis C Virus Treatment. (PubMed, Antimicrob Agents Chemother) - "Levels of liver triphosphate following oral administration of GS2 in animals were higher than GS-6620 even when administered under optimal conditions for GS-6620 absorption. Combined these properties suggest that GS2 will have better oral absorption in the clinic when administered in a solid dosage form and the potential to extend the clinical proof of concept obtained with GS-6620."

Journal

Metabolism and pharmacokinetics of the anti-HCV nucleotide prodrug GS-6620 (Antimicrob Agents Chemother) - "In first in human clinical trials, oral administration of GS-6620 resulted in poor plasma exposure relative to that observed in dogs and large pharmacokinetic and pharmacodynamic variability. While a double prodrug approach including a 3' -isobutyryl ester provided higher intrinsic intestinal permeability, this substitution appeared to be a metabolic liability resulting in extensive intestinal metabolism and relatively poor oral absorption in humans."

Review