Promising antiviral protease inhibitors: With no vaccine or proven effective drug against the virus that causes coronavirus disease 2019 (COVID-19), scientists are racing to find clinical antiviral treatments. A promising drug target is the viral main protease M ^pro , which plays a key role in viral replication and transcription. Dai et al. designed two inhibitors, 11a and 11b, based on analyzing the structure of the M ^pro active site. Both strongly inhibited the activity of M ^pro and showed good antiviral activity in cell culture. Compound 11a had better pharmacokinetic properties and low toxicity when tested in mice and dogs, suggesting that this compound is a promising drug candidate. Science , this issue p. 1331

Long Stokes shift dyes that minimize cross-talk between the excitation source and fluorescent emission to improve the signal-to-background ratio are highly desired for fluorescence imaging. However, simple small molecular dyes with large Stokes shift (more than 120 nanometers) and near-infrared (NIR) emissions have been rarely reported so far. Here, inspired by the chromophore chemical structure of fluorescent proteins, we designed and synthesized a series of styrene oxazolone dyes (SODs) with simple synthetic methods, which show NIR emissions (>650 nanometers) with long Stokes shift (ranged from 136 to 198 nanometers) and small molecular weight (<450 daltons). The most promising SOD9 shows rapid renal excretion and blood-brain barrier passing properties. After functioning with the mitochondrial-targeted triphenylphosphonium (TPP) group, the resulting SOD9-TPP can be engineered for head-neck tumor imaging, fluorescence image–guided surgery, brain neuroimaging, and on-site pathologic analysis. In summary, our findings add an essential small molecular dye category to the classical dyes.

Human noroviruses (HuNoVs) are the most common cause of viral gastroenteritis resulting annually in ~219,000 deaths and a societal cost of ~USD 60 billion, and no antivirals or vaccines are available. Here, we assess the anti-norovirus activity of new peptidomimetic aldehydes related to the protease inhibitor rupintrivir. The early hit compound 4 inhibited the replication of murine norovirus (MNV) and the HuNoV GI.1 replicon in vitro (EC₅₀ ~1 µM) and swiftly cleared the HuNoV GI.1 replicon from the cells. Compound 4 still inhibits the proteolytic activity. We selected a resistant GI.1 replicon, with a mutation (I109V) in a highly conserved region of the viral protease, conferring a low yield of resistance against compound 4 and rupintrivir. After testing new derivatives, compound 10d was the most potent (EC₅₀ nanomolar range). Molecular docking indicated that the aldehyde group of compounds 4 and 10d bind with Cys139 in the HuNoV 3CL protease by a covalent linkage. Finally, compound 10d inhibited the replication of HuNoV GII.4 in infected zebrafish larvae, and PK studies in mice showed an adequate profile.

A traceless approach to quinolin-4(1H)-one scaffolds through Rh(III)-catalyzed redox-neutral [3+3] cyclization of N-nitrosoanilines with cyclopropenones has been achieved. This protocol features short reaction time and atom-economical combination without extra additives, which can be further applied in the construction of privileged heterocyclic compounds in pharmaceutical chemistry.

Human adenovirus (HAdV) is a significant viral pathogen that causes severe acute respiratory infections (SARIs) in children and immunocompromised patients. Currently, no specific treatment options are available for HAdV infections. This study used a green fluorescence protein-based, high-throughput screening (HTS) assay on a botanical drug library containing 3697 botanical compounds to identify agents that could inhibit HAdV. Four compounds with anti-HAdV-C5 activity in the low-micromolar range were identified and inhibited other wild-type HAdVs known to cause SARIs. Among these compounds, 13-methylberberine chloride presented the highest select index values. Berberine is a commercially available natural product-derived isoquinoline alkaloid with multiple pharmacological effects and is widely used in Asian countries. We systematically evaluated the anti-HAdV activity of six berberine-derived compounds in vitro and performed a time-of-drug-addition assay to explore their antiviral modes of action. Mechanistic studies revealed that berberine and its analogs inhibit HAdV replication by downregulating the MAPK signaling pathway, particularly ERK activation, which is crucial for viral replication and progeny production. Our findings suggest that berberine is a promising candidate for the development of anti-HAdV therapies.