Identification of N- and C-3-Modified Laudanosoline Derivatives as Novel Influenza PAN Endonuclease Inhibitors.

Influenza PAN inhibitors are of particular importance in current efforts to develop a new generation of antiviral drugs due to the growing emergence of highly pathogenic influenza viruses and the resistance to existing antiviral inhibitors. Herein, we design and synthesize a set of 1,3-cis-N-substituted-1,2,3,4-tetrahydroisoquinoline derivatives to enhance their potency by further exploiting the pockets 3 and 4 in the PAN endonuclease based on the hit d,l-laudanosoline. Particularly, the lead compound 35 exhibited potent and broad anti-influenza virus effects with EC50 values ranging from 0.43 to 1.12 µM in vitro and good inhibitory activity in a mouse model. Mechanistic studies demonstrated that 35 could bind tightly to the PAN endonuclease of RNA-dependent RNA polymerase, thus blocking the viral replication to exert antiviral activity. Overall, our study might establish the importance of 1,2,3,4-tetrahydroisoquinoline-6,7-diol-based derivatives for the development of novel PAN inhibitors of influenza viruses.

Identification, optimization, and biological evaluation of 3-O-ß-chacotriosyl ursolic acid derivatives as novel SARS-CoV-2 entry inhibitors by targeting the prefusion state of spike protein.

The COVID-19 pandemic generates a global threat to public health and continuously emerging SARS-CoV-2 variants bring a great challenge to the development of both vaccines and antiviral agents. In this study, we identified UA-18 and its optimized analog UA-30 via the hit-to-lead strategy as novel SARS-CoV-2 fusion inhibitors. The lead compound UA-30 showed potent antiviral activity against infectious SARS-CoV-2 (wuhan-HU-1 variant) in Vero-E6 cells and was also effective against infection of diverse pseudotyped SARS-CoV-2 variants with mutations in the S protein including the Omicron and Delta variants. More importantly, UA-30 might target the cavity between S1 and S2 subunits to stabilize the prefusion state of the SARS-CoV-2 S protein, thus leading to interfering with virus-cell membrane fusion. This study offers a set of novel SARS-CoV-2 fusion inhibitors against SARS-CoV-2 and its variants based on the 3-O-ß-chacotriosyl UA skeleton.

Prevalence and clinical characteristics of COVID-19 in inpatients with schizophrenia in Wuhan, China.

BACKGROUND: In contrast to many Western countries, China has maintained its large psychiatric hospitals. The prevalence and clinical characteristics of coronavirus disease 2019 (COVID-19) in inpatients with schizophrenia (SCZ) are unclear. AIM: To assess the prevalence of COVID-19 among inpatients with SCZ and compare the infected to uninfected SCZ patients in a Wuhan psychiatric hospital. METHODS: We retrospectively collected demographic characteristics and clinical profiles of all SCZ patients with COVID-19 at Wuhan's Youfu Hospital. RESULTS: Among the 504 SCZ patients, 84 had COVID-19, and we randomly sampled 174 who were uninfected as a comparison group. The overall prevalence of COVID-19 in SCZ patients was 16.7%. Among the 84 SCZ patients with confirmed COVID-19, the median age was 54 years and 76.2% were male. The most common symptom was fever (82%), and less common symptoms were cough (31%), poor appetite (20%), and fatigue (16%). Compared with SCZ patients without COVID-19, those with COVID-19 were older (P = 0.006) and significantly lighter (P = 0.002), and had more comorbid physical diseases (P = 0.001). Surprisingly, those infected were less likely to be smokers (< 0.001) or to be treated with clozapine (P = 0.03). Further logistic regression showed that smoking [odds ratio (OR) = 5.61], clozapine treated (OR = 2.95), and male (OR = 3.48) patients with relatively fewer comorbid physical diseases (OR = 0.098) were at a lower risk for COVID-19. SCZ patients with COVID-19 presented primarily with fever, but only one-third had a cough, which might otherwise be the most common mode of transmission between individuals. CONCLUSION: Two unexpected protective factors for COVID-19 among SCZ inpatients are smoking and clozapine treatment.

Synthesis and SARs of dopamine derivatives as potential inhibitors of influenza virus PAN endonuclease.

Currently, influenza PAN endonuclease has become an attractive target for development of new drugs to treat influenza infections. Herein we report the discovery of new PAN endonuclease inhibitors derived from a chelating agent dopamine moiety. A series of dopamine amide derivatives and their conformationally constrained 1,2,3,4-tetrahydroisoquinoline-6,7-diol-based analogs were elaborated and assayed against influenza virus A/WSN/33 (H1N1). Most compounds exhibited moderate to excellent antiviral activities, generating a preliminary SARs. Among them, compounds 14 and 19 showed stronger anti-IAV activity compared with the reference Peramivir. Moreover, 14 and 19 demonstrated a concentration-dependent inhibition of PAN endonuclease based on both FRET assay and SPR assay. Docking studies were also performed to elucidate the binding mode of 14 and 19 with the PAN protein and to identify amino acids involved in their mechanism of action, which were well consistent with the biological data. This finding was beneficial to laying the foundation for the rational development of more effective PAN endonuclease inhibitors.