SARS-CoV-2 Mpro inhibitors with antiviral activity in a transgenic mouse model.

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continually poses serious threats to global public health. The main protease (Mpro) of SARS-CoV-2 plays a central role in viral replication. We designed and synthesized 32 new bicycloproline-containing Mpro inhibitors derived from either boceprevir or telaprevir, both of which are approved antivirals. All compounds inhibited SARS-CoV-2 Mpro activity in vitro, with 50% inhibitory concentration values ranging from 7.6 to 748.5 nM. The cocrystal structure of Mpro in complex with MI-23, one of the most potent compounds, revealed its interaction mode. Two compounds (MI-09 and MI-30) showed excellent antiviral activity in cell-based assays. In a transgenic mouse model of SARS-CoV-2 infection, oral or intraperitoneal treatment with MI-09 or MI-30 significantly reduced lung viral loads and lung lesions. Both also displayed good pharmacokinetic properties and safety in rats.

Discovery of Potent and Selective Inhibitors of Cdc2-Like Kinase 1 (CLK1) as a New Class of Autophagy Inducers.

Autophagy inducers represent new promising agents for the treatment of a wide range of medical illnesses. However, safe autophagy inducers for clinical applications are lacking. Inhibition of cdc2-like kinase 1 (CLK1) was recently found to efficiently induce autophagy. Unfortunately, most of the known CLK1 inhibitors have unsatisfactory selectivity. Herein, we report the discovery of a series of new CLK1 inhibitors containing the 1H-[1,2,3]triazolo[4,5-c]quinoline scaffold. Among them, compound 25 was the most potent and selective, with an IC50 value of 2 nM against CLK1. The crystal structure of CLK1 complexed with compound 25 was solved, and the potency and kinase selectivity of compound 25 were interpreted. Compound 25 was able to induce autophagy in in vitro assays and displayed significant hepatoprotective effects in the acetaminophen (APAP)-induced liver injury mouse model. Collectively, due to its potency and selectivity, compound 25 could be used as a chemical probe or agent in future mechanism-of-action or autophagy-related disease therapy studies.

From Lead to Drug Candidate: Optimization of 3-(Phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine Derivatives as Agents for the Treatment of Triple Negative Breast Cancer.

Herein we report the sophisticated process of structural optimization toward a previously disclosed Src inhibitor, compound 1, which showed high potency in the treatment of triple negative breast cancer (TNBC) both in vitro and in vivo but had considerable toxicity. A series of 3-(phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine derivatives were synthesized. In vitro cell-based phenotypic screening together with in vivo assays and structure-activity relationship (SAR) studies finally led to the discovery of N-(3-((4-amino-1-(trans-4-hydroxycyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)ethynyl)-4-methylphenyl)-4-methyl-3-(trifluoromethyl)benzamide (13an). 13an is a multikinase inhibitor, which potently inhibited Src (IC50 = 0.003 µM), KDR (IC50 = 0.032 µM), and several kinases involved in the MAPK signal transduction. This compound showed potent anti-TNBC activities both in vitro and in vivo, and good pharmacokinetic properties and low toxicity. Mechanisms of action of anti-TNBC were also investigated. Collectively, the data obtained in this study indicate that 13an could be a promising drug candidate for the treatment of TNBC and hence merits further studies.

[Two-step image registration based on control volumes].

OBJECTIVE: To increase the accuracy of beam targeting and improve the dose distributions in radiotherapy using a robust image registration algorithm based on control volumes. METHODS: Control volume mapping and thin-plate spline deformable transformation were combined. The use of the control volumes increased the accuracy for the deformable registration. A bi-directional mapping method was also employed to correctly match the control volumes. RESULTS: The clinical images were simulated using the proposed two-step image registration algorithm. The simulation results indicated that the registration algorithm was robust and universal, even in cases of obvious deformation. CONCLUSIONS: The algorithm provides a more convenient and robust resolution as compared to manual landmark-based methods and single-step deformable transformations, and may help in automatic image registration in radiation therapy.

[A new method for predicting anterior chamber depth in intraocular lens implantation].

OBJECTIVE: To propose a method for predicting the postoperative anterior chamber depth value (ACD) based on the evaluation standard of contrast sensitivity function (CSF). METHODS: In a personalized eye model, the natural lens was replaced with an artificial lens, and the tracing method based on ZEMAX software was utilized to simulate the pseudophakic optical system. The best MTF curve was obtained through optical optimization to calculate the CSF and determine the best contrast sensitivity (CS) curve. The best ACD value was acquired according to the CSF curve. The data form 10 cataract cases without retinal diseases were obtained and the postoperative ACD value was predicted using Holladay, Hoffer Q, SRK/T and the proposed method. RESULTS: Consistency analysis of the results showed that all the ACD values predicated by the 4 methods fell in 95% consistency within the boundaries, and the differences in the largest absolute value between the 3 methods (Holladay, Hoffer Q, and SRK/T) and the proposed method were 0.73 mm, 0.65 mm, and 0.68 mm, and the calculation results of the mean value were 5.846 mm, 5.804 mm, and 5.825 mm. Clinically, the two methods were deemed to have good consistency. CONCLUSION: The proposed method establishes a connection between the contrast sensitivity curve and ACD to allow better refraction adjustment for the patients.

[Application of 3D FIESTA sequence in magnetic resonance sialography for obstructive salivary diseases].

OBJECTIVE: To investigate the value of 3D FIESTA sequence in magnetic resonance sialography (MRS) in the diagnosis of obstructive salivary diseases. METHODS: Eleven patients with obstructive salivary diseases underwent MRS, and three-dimensional (3D) reconstruction and virtual endoscopic images of the salivary gland ducts were obtained after MRS data post-processing for comparison with those of sialoendoscopy. RESULTS: The diagnostic accuracy of MRS was 72.7% for obstructive salivary diseases. The virtual endoscopy provided a visual field highly consistent with that by sialoendoscopy. CONCLUSION: MRS is capable of visualizing the tracts of salivary glands. MR virtual endoscopy can provide sufficient morphological and pathological data for preoperative assessment of salivary operations with sialoendoscopy.

[Magnetic resonance imaging of bone and joint transfixed with stainless steel lag screws].

OBJECTIVE: To explore the method of displaying the bone and joint structures transfixed with stainless steel lag screws using magnetic resonance imaging (MRI), 2 patients whose knee joints (and ankle joint in one case) were transfixed with stainless steel underwent MRI with FSE-XL pulse sequence. The images clearly displayed the bones, ligaments and articular cartilage around the stainless steel materials, demonstrating the efficacy of FSE-XL pulse sequence in evaluation of the anatomical features of the bones and joints transfixed with stainless steel materials.

[Nonlinear analysis of epileptic multichannel EEG].

OBJECTIVE: To study the difference between the nonlinear eigenvalue of epileptic patients and normal subjects for accurate identification of epileptic EEG signal. METHODS: Multivariable phase space reconstruction technique was employed to analyze the EEG of epileptic patients for estimating the correlation dimension(D(2)), which was one of the most often used parameters in quantitative discretion of complicated nonlinear dynamics system. RESULT AND CONCLUSION: The correlation dimension is an important eigenvalue for epileptic EEG identification.

[Design of the medical record database of diabetes mellitus].

The system requirement of the clinical record database of diabetes mellitus was analyzed, the functional module built and the design scheme established on the basis of the general design objective for a distributed database with distributed objects.

[Study of fuzzy analytical system for physiological signals during sleep].

A new approach to sleep analysis based on fuzzy prediction theory is described. This article gives a general introduction to detection and processing of biologic signals with LabVIEW software, and the application of the designed fuzzy measurement system in fuzzy prediction analysis of the physiological signals recorded during sleep. The results of trials of the fuzzy prediction analysis demonstrated the reliability of this method. LabVIEW-based fuzzy prediction analysis can be helpful for early diagnosis, monitoring and prognostic assessment of some diseases, and may be valuable in the analysis of the physiologic signals of patients with obstructive sleep apnea syndrome (OSAS) during sleep.

[Evaluation method of CT number linearity].

OBJECTIVE: To explore the method for computed tomography (CT) number linearity evaluation. METHODS: The model CTP401 of Catphan500 phantom was adopted to test 43 sets of CT scanners under the same scanning conditions. 1- and 2-order curve fitting of the testing results of each scanner were performed, with the bending of the 2-order fitted curve defined as the degree of CT number non-linearity and the slope of the linear fitting as contrast scale. The 2-norms of the fitting coefficients were calculated for the purpose of fitting quality evaluation. MATLAB 6.1 was employed for programming. RESULTS: The 2-norm of the fitting coefficients of the 2-order fitting curve was approximately 1/10 of that of corresponding linear fitting, indicating that 2-order fitting accorded better to the parent population distribution pattern. The degree of the non-linearity was manifested by the bending of the 2-order fitting curve that increased monotonously with the 2-norm of the corresponding linear fitting. CONCLUSION: It is statistically valid to define CT number non-linearity and contrast scale on the basis of 1 and 2-order fittings of the testing results, which well serves the purpose of quantitative analysis.