Spiro-Azetidine Oxindoles as Long-Acting Injectables for Pre-Exposure Prophylaxis against Respiratory Syncytial Virus Infections.

Respiratory syncytial virus (RSV) is a major cause of hospitalization in infants, the elderly, and immune-compromised patients. While a half-life extended monoclonal antibody and 2 vaccines have recently been approved for infants and the elderly, respectively, options to prevent disease in immune-compromised patients are still needed. Here, we describe spiro-azetidine oxindoles as small molecule RSV entry inhibitors displaying favorable potency, developability attributes, and long-acting PK when injected as an aqueous suspension, suggesting their potential to prevent complications following RSV infection over a period of 3 to 6 months with 1 or 2 long-acting intramuscular (IM) or subcutaneous (SC) injections in these immune-compromised patients.

Homeostasis, injury, and recovery dynamics at multiple scales in a self-organizing mouse intestinal crypt.

The maintenance of the functional integrity of the intestinal epithelium requires a tight coordination between cell production, migration, and shedding along the crypt-villus axis. Dysregulation of these processes may result in loss of the intestinal barrier and disease. With the aim of generating a more complete and integrated understanding of how the epithelium maintains homeostasis and recovers after injury, we have built a multi-scale agent-based model (ABM) of the mouse intestinal epithelium.

A dynamic model of the intestinal epithelium integrates multiple sources of preclinical data and enables clinical translation of drug-induced toxicity.

We have built a quantitative systems toxicology modeling framework focused on the early prediction of oncotherapeutic-induced clinical intestinal adverse effects. The model describes stem and progenitor cell dynamics in the small intestinal epithelium and integrates heterogeneous epithelial-related processes, such as transcriptional profiles, citrulline kinetics, and probability of diarrhea. We fitted a mouse-specific version of the model to quantify doxorubicin and 5-fluorouracil (5-FU)-induced toxicity, which included pharmacokinetics and 5-FU metabolism and assumed that both drugs led to cell cycle arrest and apoptosis in stem cells and proliferative progenitors.

Safety, Tolerability, and Pharmacokinetics of JNJ-1802, a Pan-serotype Dengue Direct Antiviral Small Molecule, in a Phase 1, Double-Blind, Randomized, Dose-Escalation Study in Healthy Volunteers.

Background: Dengue is a growing global health threat with no specific antiviral drugs available for treatment or prophylaxis. This first-in-human, double-blind, randomized, placebo-controlled study aimed to examine the safety, tolerability, and pharmacokinetics of increasing single and multiple oral doses of JNJ-1802, a pan-serotype dengue antiviral small molecule.

Methods: Eligible healthy participants (18-55 years of age) were randomized to receive oral JNJ-1802 in fasted conditions as (1) single doses (50-1200 mg; n = 29) or placebo (n = 10); or (2) once-daily doses (50-560 mg for 10 consecutive days or 400 mg for 31 days; n = 38) or placebo (n = 9).

Mouse organoids as an in vitro tool to study the in vivo intestinal response to cytotoxicants.

Cross-species comparison of drug responses at the organoid level could help to determine the human relevance of findings from animal studies. To this end, we first need to evaluate the in vitro to in vivo translatability of preclinical organoids. Here, we used 5-fluorouracil (5-FU) as an exemplar drug to test whether the in vivo gut response to this cytotoxicant was preserved in murine intestinal organoids.