作者: Zhang, Yuntao ; Jin, Dong-Yan ; Luo, Peng ; Hinson Cheung, Pak-Hin ; Ni, Tao ; Ye, Zi-Wei ; Gray, Victor Sebastien ; Wang, Junjue ; Zhang, Hongzhuo ; Ong, Chon Phin ; Li, Weixin ; Tang, Kaiming ; Yuan, Shuofeng ; Cao, Hehe ; Ling, Guang Sheng ; Zhang, Ming ; Chan, Chi Ping

BACKGROUNDLive attenuated vaccines against SARS-CoV-2 activate all phases of host immunity resembling a natural infection and they block viral transmission more efficiently than existing vaccines in human use. In our prior work, we characterised an attenuated SARS-CoV-2 variant, designated d16, which harbours a D130A mutation in the NSP16 protein, inactivating its 2'-O-methyltransferase function. The d16 variant has demonstrated an ability to induce both mucosal and sterilising immunity in animal models. However, further investigation is required to identify any additional modifications to d16 that could mitigate concerns regarding potential virulence reversion and the suboptimal regulation of the proinflammatory response.METHODSMutations were introduced into molecular clone of SARS-CoV-2 and live attenuated virus was recovered from cultured cells. Virological, biochemical and immunological assays were performed in vitro and in two animal models to access the protective efficacies of the candidate vaccine strain.FINDINGSHere we describe evaluation of a derivative of d16. We further modified the d16 variant by inverting the open reading frame of the ORF3a accessory protein, resulting in the d16i3a strain. This modification is anticipated to enhance safety and reduce pathogenicity. d16i3a appeared to be further attenuated in hamsters and transgenic mice compared to d16. Intranasal vaccination with d16i3a stimulated humoural, cell-mediated and mucosal immune responses, conferring sterilising protection against SARS-CoV-2 Delta and Omicron variants in animals. A version of d16i3a expressing the XBB.1.16 spike protein further expanded the vaccine's protection spectrum against circulating variants. Notably, this version has demonstrated efficacy as a booster in hamsters, providing protection against Omicron subvariants and achieving inhibition of viral transmission.INTERPRETATIONOur work established a platform for generating safe and effective live attenuated vaccines by dual inactivation of NSP16 and ORF3a of SARS-CoV-2.FUNDINGThis work was supported by National Key Research and Development Program of China (2021YFC0866100, 2023YFC3041600, and 2023YFE0203400), Hong Kong Health and Medical Research Fund (COVID190114, CID-HKU1-9, and 23220712), Hong Kong Research Grants Council (C7142-20GF and T11-709/21-N), Hong Kong Innovation and Technology Commission grant (MHP/128/22), Guangzhou Laboratory (EKPG22-01) and Health@InnoHK (CVVT). Funding sources had no role in the writing of the manuscript or the decision to submit it for publication.

2025-04-01·Acta Pharmacologica Sinica

Discovery of novel dual-target inhibitors of LSD1/EGFR for non-small cell lung cancer therapy

Article

作者: Sun, Ming-Ming ; Zhang, Rui-Li ; Lin, Jian-Ping ; Wei, Yu ; Yang, Li-Hong ; Wang, Lin ; Shan, Chang-Liang

AbstractHistone lysine-specific demethylase 1 (LSD1) is overexpressed in various solid and hematological tumors, suggesting its potential as a therapeutic target, but there are currently no LSD1 inhibitors available on the market. In this study we employed a computer-guided approach to identify novel LSD1/EGFR dual inhibitors as a potential therapeutic agent for non-small cell lung cancer. Through a multi-stage virtual screening approach, we found L-1 and L-6, two compounds with unique scaffolds that effectively inhibit LSD1 with IC50 values of 6.24 and 9.26 μM, respectively. Using molecular similarity-based screening, 48 analogs of L-1 and L-6 were retrieved from ChemDiv library, 18 analogs were selected for biological activity analysis. Eight compounds showed weaker inhibitory activity against LSD1, with IC50 values of 19.79 – 35.70 μM. Moreover, L-1, L-6, and two analogs of L-6 (D-14 and D-16) were found to inhibit triple-mutant EGFR (L858R/T790M/C797S) with potencies ranging from 5.01 to 86.70 μM, and to inhibit double-mutant EGFR (T790M/L858R) with potencies ranging from 2.06 to 64.36 μM. In BaF3 cells that stably express EGFR (L858R/T790M/C797S), the inhibitory activity of L-1, L-6, D-14 and D-16 ranged from 2.72 to 8.99 μM. L-1 that shows the highest biological activity across BaF3 cell, mutant EGFR kinase and LSD1 assays due to its dual targeting of LSD1/EGFR, emerges as a promising lead compound for non-small cell lung cancer treatment. This study demonstrates that L-1 efficiently inhibits lung cancer growth in vitro and in vivo, suggesting it as a potential lead for non-small cell lung cancer treatment, highlighting the utility of virtual screening methods in discovering multi-target inhibitors and strategies for other diseases.

2025-03-01·Veterinary Microbiology

Whole-canine neutralizing antibodies generated by single B cell antibody technology elicit therapeutic protection against canine distemper virus infection

Article

作者: Zhao, Ling ; Wang, Sheng ; Sheng, Wei ; Wang, Zhihao ; Zhang, Chengguang ; Zhou, Hongbo ; Wang, Zhichen ; Shi, Pengfei ; Zou, Jiahui

Canine distemper virus (CDV) causes a highly contagious and fatal disease in domestic and wild carnivores. Currently, vaccination is the primary method for preventing canine distemper. However, incidents of vaccine immunization failures continue to be reported. There are no specific and effective treatment agents available for canine distemper infection. Neutralizing antibodies offer a potential approach for the treatment of viral diseases. In this study, single B cell antibody technology was applied to obtain whole-canine antibodies against CDV. 7 monoclonal antibodies were screened and showed high binding affinity to CDV hemagglutinin (H) protein, with D16 and F53 exhibited high specificity and neutralizing activity against CDV. Furthermore, D16 exhibited effective therapeutic potential in dogs subjected to lethal dose CDV attacks in vivo. In conclusion, our study offers an alternative approach for acquiring neutralizing antibody and provides a promising new strategy for the treatment of CDV infection.

100 项与 D-16(Nankai University) 相关的药物交易

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