Influenza viruses constitute a major health threat and economic burden globally, frequently exacerbated by preexisting or rapidly emerging resistance to antiviral therapeutics. To address the unmet need of improved influenza therapy, we have created EIDD-2801, an isopropylester prodrug of the ribonucleoside analog N4-hydroxycytidine (NHC, EIDD-1931) that has shown broad anti-influenza virus activity in cultured cells and mice. Pharmacokinetic profiling demonstrated that EIDD-2801 was orally bioavailable in ferrets and nonhuman primates. Therapeutic oral dosing of influenza virus–infected ferrets reduced group pandemic 1 and group 2 seasonal influenza A shed virus load by multiple orders of magnitude and alleviated fever, airway epithelium histopathology, and inflammation, whereas postexposure prophylactic dosing was sterilizing. Deep sequencing highlighted lethal viral mutagenesis as the underlying mechanism of activity and revealed a prohibitive barrier to the development of viral resistance. Inhibitory concentrations were low nanomolar against influenza A and B viruses in disease-relevant well-differentiated human air-liquid interface airway epithelia. Correlating antiviral efficacy and cytotoxicity thresholds with pharmacokinetic profiles in human airway epithelium models revealed a therapeutic window >1713 and established dosing parameters required for efficacious human therapy. These data recommend EIDD-2801 as a clinical candidate with high potential for monotherapy of seasonal and pandemic influenza virus infections. Our results inform EIDD-2801 clinical trial design and drug exposure targets.

Morbidity and mortality resulting from influenza-like disease are a threat, especially for older adults. To improve case management, next-generation broad-spectrum antiviral therapeutics that are efficacious against major drivers of influenza-like disease, including influenza viruses and respiratory syncytial virus (RSV), are urgently needed. Using a dual-pathogen high-throughput screening protocol for influenza A virus (IAV) and RSV inhibitors, we have identified -hydroxycytidine (NHC) as a potent inhibitor of RSV, influenza B viruses, and IAVs of human, avian, and swine origins. Biochemical polymerase assays and viral RNA sequencing revealed that the ribonucleotide analog is incorporated into nascent viral RNAs in place of cytidine, increasing the frequency of viral mutagenesis. Viral passaging in cell culture in the presence of an inhibitor did not induce robust resistance. Pharmacokinetic profiling demonstrated dose-dependent oral bioavailability of 36 to 56%, sustained levels of the active 5'-triphosphate anabolite in primary human airway cells and mouse lung tissue, and good tolerability after extended dosing at 800 mg/kg of body weight/day. The compound was orally efficacious against RSV and both seasonal and highly pathogenic avian IAVs in mouse models, reducing lung virus loads and alleviating disease biomarkers. Oral dosing reduced IAV burdens in a guinea pig transmission model and suppressed virus spread to uninfected contact animals through direct transmission. Based on its broad-spectrum efficacy and pharmacokinetic properties, NHC is a promising candidate for future clinical development as a treatment option for influenza-like diseases.

We report a molecular design that provides an intravenously injectable organic radical contrast agent (ORCA) that has molecular r1 ≈ 5 mM−1s−1. The ORCA is based on spirocyclohexyl nitroxide radicals and polyethylene glycol chains conjugated to a generation 4 polypropylenimine dendrimers scaffold. The metal-free ORCA has a long shelf-life and provides selectively enhanced MRI in mice for over 1 h.

Advances in drug potency and tailored therapeutics are promoting pharmaceutical manufacturing to transition from a traditional batch paradigm to more flexible continuous processing. Here we report the development of a multistep continuous-flow CGMP (current good manufacturing practices) process that produced 24 kilograms of prexasertib monolactate monohydrate suitable for use in human clinical trials. Eight continuous unit operations were conducted to produce the target at roughly 3 kilograms per day using small continuous reactors, extractors, evaporators, crystallizers, and filters in laboratory fume hoods. Success was enabled by advances in chemistry, engineering, analytical science, process modeling, and equipment design. Substantial technical and business drivers were identified, which merited the continuous process. The continuous process afforded improved performance and safety relative to batch processes and also improved containment of a highly potent compound.

Of 226 donor cattle treated with PMSG to induce superovulation, 76.5% responded with 3 or more ovulations. Flushing at surgery or slaughter 10-16 days after oestrus recovered eggs and embryos that represented 49.3% of the number of ovulations. Of those recovered, 73.3% were embryos, an average yield of 4.0 embryos/treated cow or 4.8 embryo/flushed cow. The location of eggs and embryos was determined in 65 of the donors. Embryos and unfertilized eggs (6.1% of those recovered) were occasionally found in the oviducts. Empty zonae pellucidae were also found in the uterus on all days. The lengths, or diameters, of embryos were extremely variable within days and within donors, but mean values indicated logarithmic growth between Days 10 and 16. Eighty-four synchronous (+/- 1 day) recipients received single embryos, and 51 recipients twin embryos, by surgical transfer. Pregnancies were obtained in recipients up to Day 16 but not on Day 17, indicating the stage by which an embryo must be present to prevent luteolysis. The overall pregnancy rate at Day 42 was 50.4% and further 18.1% of the recipients exhibited extended oestrous cycles. Of 35 recipients that were allowed to go to term, 12 lost their pregnancies, most often between Days 42 and 63.

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With metal halide perovskite solar cells (PSCs) now reaching device efficiencies >23%, more emphasis must now shift toward addressing their device stability. Recently, a triarylamine-based organic hole-transport material (HTM) doped with its oxidized salt analogue (EH44/EH44-ox) led to unencapsulated PSCs with high stability in ambient conditions. Here we report criteria for triarylamine-based organic HTMs formulated with stable oxidized salts as hole-transport layer (HTL) for increased PSC thermal stability. The triarylamine-based dopants must contain at least two para-electron-donating groups for radical cation stabilization to prevent impurity formation that leads to reduced PSC performance. The stability of unencapsulated devices prepared using these new HTMs stressed under constant load and illumination far outperforms that of both EH44/EH44-ox and Li+-doped spiro-OMeTAD controls at 50 °C. Furthermore, the ability to mix and match these dopants with a nonidentical small-molecule-based HTL matrix broadens the design scope for highly stable and cost-effective PSCs without sacrificing performance.

A single set of reaction conditions for the palladium-catalyzed amination of a wide variety of (hetero)aryl halides using primary alkyl amines has been developed. By combining the exceptionally high reactivity of the Pd-PEPPSI-IPent(Cl) catalyst (PEPPSI=pyridine enhanced precatalyst preparation, stabilization, and initiation) with the soluble and nonaggressive sodium salt of BHT (BHT=2,6-di-tert-butyl-hydroxytoluene), both six- and five-membered (hetero)aryl halides undergo efficient and selective amination.