Objective To investigate the role of autophagy in the development of diabetic cataract by detecting the expression of autophagy-related factors (BECN1,LC3B,P62) in diabetic mouse lens epithelial cells.Methods Eighty C57BL/6 male mice were selected.Fifty C57 mice were consecutively dosed with streptozotocin (STZ) 50 mg/ (kg · d) by intraperitoneal injection to induce type 1 diabetes mellitus model,and served as the model group;the remaining 30 mice were injected with appropriate dose of citrate buffer,and served as the control group.The fasting plasma glucose was tested by collecting the caudal vein blood in the model group.The morphological changes of autophagy of lens epithelial cells were observed by transmission electron microscopy.The expression and localization of LC3B and P62 protein were detected by immunohistochemistry.PCR was used to detect the expression of BECN1,LC3B and P62 mRNA in the anterior capsule.The relative expression of autophagy-related proteins in the anterior capsule was detected by Western blot.The use of animals complied with Regulations on the Management of Experimental Ainimals from Shandong Eye Institute.Results Compared with the control group,transmission electron microscopy revealed that the autophagosomes of lens epithelial cells in model group was large and contained more mitochondria.Immunohistochemical method showed that the expression of LC3B and P62 proteins in the anterior capsule tissue of experiment group was stronger than that of the control group.The relative expression level of BECN1,LC3B and P62 mRNA in the experiment group was 1.48±0.10,2.62±0.15 and 1.89±0.20,respectively,which was higher than 1.10±0.02,1.10±0.05 and 1.01±0.01 in the control group,with significant differences between the two groups (t =6.64,14.25,6.14;all at P ＜ 0.05).The relative expression of BECN1,LC3B and P62 protein in the experiment group was 1.50±0.10,1.24±0.09 and 3.19± 1.04,respectively,which was higher than 1.00±0.00,1.00±0.00 and 1.00±0.00 in the control group,with significant differences between the two groups (t =8.75,6.10,3.65;all at P＜0.05).Conclusions The phenomenon of autophagy in lens epithelial cells of diabetic mice is abnormal,and autophagy dysfunction may play an important role in the formation of diabetic cataract.

Indolylarylsulfones (IASs) are classical HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) with a unique scaffold and possess potent antiviral activity. To address the high cytotoxicity and improve safety profiles of IASs, we introduced various sulfonamide groups linked by alkyl diamine chain to explore the entrance channel of non-nucleoside inhibitors binding pocket. 48 compounds were designed and synthesized to evaluate their anti-HIV-1 activities and reverse transcriptase inhibition activities. Especially, compound R₁₀L₄ was endowed with significant inhibitory activity towards wild-type HIV-1 (EC_50(WT) = 0.007 μmol/L, SI = 30,930) as well as a panel of single-mutant strains exemplified by L100I (EC₅₀ = 0.017 μmol/L, SI = 13,055), E138K (EC₅₀ = 0.017 μmol/L, SI = 13,123) and Y181C (EC₅₀ = 0.045 μmol/L, SI = 4753) which were superior to Nevirapine and Etravirine. Notably, R₁₀L₄ was characterized with significantly reduced cytotoxicity (CC₅₀ = 216.51 μmol/L) and showed no remarkable in vivo toxic effects (acute and subacute toxicity). Moreover, the computer-based docking study was also employed to characterize the binding mode between R₁₀L₄ and HIV-1 RT. Additionally, R₁₀L₄ presented an acceptable pharmacokinetic profile. Collectively, these results deliver precious insights for next optimization and indicate that the sulfonamide IAS derivatives are promising NNRTIs for further development.

Novel therapies are urgently needed to improve global treatment of SARS-CoV-2 infection. Herein, we briefly provide a concise report on the medicinal chemistry strategies towards the development of effective SARS-CoV-2 inhibitors with representative examples in different strategies from the medicinal chemistry perspective.

The main protease (M^pro) of SARS-CoV-2 is an attractive target in anti-COVID-19 therapy for its high conservation and major role in the virus life cycle. The covalent M^pro inhibitor nirmatrelvir (in combination with ritonavir, a pharmacokinetic enhancer) and the non-covalent inhibitor ensitrelvir have shown efficacy in clinical trials and have been approved for therapeutic use. Effective antiviral drugs are needed to fight the pandemic, while non-covalent M^pro inhibitors could be promising alternatives due to their high selectivity and favorable druggability. Numerous non-covalent M^pro inhibitors with desirable properties have been developed based on available crystal structures of M^pro. In this article, we describe medicinal chemistry strategies applied for the discovery and optimization of non-covalent M^pro inhibitors, followed by a general overview and critical analysis of the available information. Prospective viewpoints and insights into current strategies for the development of non-covalent M^pro inhibitors are also discussed.