2023 Vol. 14, No. 1

A recurrent outbreak of viral infections in recent years is an important public health problem, e.g., SARS and COVID-19. However, current therapy strategy is limited to a minority of patients and associated with side effects and toxicities. Prof. Xu and her co-authors found that PAC5, derived from medical plant and as a first-in-class drug, can turns on the innate immune to eliminate the virus by binding to and activating hnRNPA2B1. The cover is in the form of a comic to describe a story of Shennong Fighting Demons used as a metaphor for the study. Legend has it that Shennong is the founder of Chinese medicine. Defeated Monsters represent viruses. Four half-eighttrigrams graphs represent inactivated hnRNPA2B1, and two complete eighttrigrams graphs represent hnRNPA2B1 activated by PAC5. The circle around Shennong metaphorically shows the binding of PAC5 to hnRNPA2B1 for antiviral immunotherapy. The cover highlights traditional Chinese medicine not only being a source of innovative drug discovery, but also being used as probes to find the new drug target.

In memory of the well-renowned Chinese cellular biologist Shien Sher-Pu
Nan Shen, Shen Liu
2023, 14(1): 1-3. doi: 10.1093/procel/pwac002
Tinker, tailor, soldier, cell: the role of C-type lectins in the defense and promotion of disease
James N. Arnold, Daniel A. Mitchell
2023, 14(1): 4-16. doi: 10.1093/procel/pwac012
C-type lectins (CTLs) represent a large family of soluble and membrane-bound proteins which bind calcium dependently via carbohydrate recognition domains (CRDs) to glycan residues presented on the surface of a variety of pathogens. The deconvolution of a cell’s glycan code by CTLs underpins several important physiological processes in mammals such as pathogen neutralization and opsonization, leukocyte trafficking, and the inflammatory response. However, as our knowledge of CTLs has developed it has become apparent that the role of this innate immune family of proteins can be double-edged, where some pathogens have developed approaches to subvert and exploit CTL interactions to promote infection and sustain the pathological state. Equally, CTL interactions with host glycoproteins can contribute to inflammatory diseases such as arthritis and cancer whereby, in certain contexts, they exacerbate inflammation and drive malignant progression. This review discusses the ‘dual agent’ roles of some of the major mammalian CTLs in both resolving and promoting infection, inflammation and inflammatory disease and highlights opportunities and emerging approaches for their therapeutic modulation.
Research Articles
High-throughput screening of SARS-CoV-2 main and papain-like protease inhibitors
Yi Zang, Mingbo Su, Qingxing Wang, Xi Cheng, Wenru Zhang, Yao Zhao, Tong Chen, Yingyan Jiang, Qiang Shen, Juan Du, Qiuxiang Tan, Peipei Wang, Lixin Gao, Zhenming Jin, Mengmeng Zhang, Cong Li, Ya Zhu, Bo Feng, Bixi Tang, Han Xie, Ming-Wei Wang, Mingyue Zheng, Xiaoyan Pan, Haitao Yang, Yechun Xu, Beili Wu, Leike Zhang, Zihe Rao, Xiuna Yang, Hualiang Jiang, Gengfu Xiao, Qiang Zhao, Jia Li
2023, 14(1): 17-27. doi: 10.1093/procel/pwac016
The global COVID-19 coronavirus pandemic has infected over 109 million people, leading to over 2 million deaths up to date and still lacking of effective drugs for patient treatment. Here, we screened about 1.8 million small molecules against the main protease (Mpro) and papain like protease (PLpro), two major proteases in severe acute respiratory syndrome-coronavirus 2 genome, and identified 1851Mpro inhibitors and 205 PLpro inhibitors with low nmol/l activity of the best hits. Among these inhibitors, eight small molecules showed dual inhibition effects on both Mpro and PLpro, exhibiting potential as better candidates for COVID-19 treatment. The best inhibitors of each protease were tested in antiviral assay, with over 40% of Mpro inhibitors and over 20% of PLpro inhibitors showing high potency in viral inhibition with low cytotoxicity. The X-ray crystal structure of SARS-CoV-2 Mpro in complex with its potent inhibitor 4a was determined at 1.8 Å resolution. Together with docking assays, our results provide a comprehensive resource for future research on anti-SARS-CoV-2 drug development.
Serosurvey for SARS-CoV-2 among blood donors in Wuhan, China from September to December 2019
Le Chang, Lei Zhao, Yan Xiao, Tingting Xu, Lan Chen, Yan Cai, Xiaojing Dong, Conghui Wang, Xia Xiao, Lili Ren, Lunan Wang
2023, 14(1): 28-36. doi: 10.1093/procel/pwac013
The emerging of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused COVID-19 pandemic. The first case of COVID-19 was reported at early December in 2019 in Wuhan City, China. To examine specific antibodies against SARS-CoV-2 in biological samples before December 2019 would give clues when the epidemic of SARS-CoV-2 might start to circulate in populations. We obtained all 88,517 plasmas from 76,844 blood donors in Wuhan between 1 September and 31 December 2019. We first evaluated the pan-immunoglobin (pan-Ig) against SARS-CoV-2 in 43,850 samples from 32,484 blood donors with suitable sample quality and enough volume. Two hundred and sixty-four samples from 213 donors were pan-Ig reactive, then further tested IgG and IgM, and validated by neutralizing antibodies against SARS-CoV-2. Two hundred and thirteen samples (from 175 donors) were only pan-Ig reactive, 8 (from 4 donors) were pan-Ig and IgG reactive, and 43 (from 34 donors) were pan-Ig and IgM reactive. Microneutralization assay showed all negative results. In addition, 213 screened reactive donors were analyzed and did not show obviously temporal or regional tendency, but the distribution of age showed a difference compared with all tested donors. Then we reviewed SARS-CoV-2 antibody results from these donors who donated several times from September 2019 to June 2020, partly tested in a previous published study, no one was found a significant increase in S/CO of antibodies against SARS-CoV-2. Our findings showed no SARS-CoV-2-specific antibodies existing among blood donors in Wuhan, China before 2020, indicating no evidence of transmission of COVID-19 before December 2019 in Wuhan, China.
A hnRNPA2B1 agonist effectively inhibits HBV and SARS-CoV-2 omicron in vivo
Daming Zuo, Yu Chen, Jian-piaoCai, Hao-Yang Yuan, Jun-Qi Wu, Yue Yin, Jing-Wen Xie, Jing-Min Lin, Jia Luo, Yang Feng, Long-Jiao Ge, Jia Zhou, Ronald J. Quinn, San-Jun Zhao, Xing Tong, Dong-Yan Jin, Shuofeng Yuan, Shao-Xing Dai, Min Xu
2023, 14(1): 37-50. doi: 10.1093/procel/pwac027
The twenty-first century has already recorded more than ten major epidemics or pandemics of viral disease, including the devastating COVID-19. Novel effective antivirals with broad-spectrum coverage are urgently needed. Herein, we reported a novel broad-spectrum antiviral compound PAC5. Oral administration of PAC5 eliminated HBV cccDNA and reduced the large antigen load in distinct mouse models of HBV infection. Strikingly, oral administration of PAC5 in a hamster model of SARS-CoV-2 omicron (BA.1) infection significantly decreases viral loads and attenuates lung inflammation. Mechanistically, PAC5 binds to a pocket near Asp49 in the RNA recognition motif of hnRNPA2B1. PAC5-bound hnRNPA2B1 is extensively activated and translocated to the cytoplasm where it initiates the TBK1-IRF3 pathway, leading to the production of type I IFNs with antiviral activity. Our results indicate that PAC5 is a novel small-molecule agonist of hnRNPA2B1, which may have a role in dealing with emerging infectious diseases now and in the future.
RBM46 is essential for gametogenesis and functions in post-transcriptional roles affecting meiotic cohesin subunits
Yue Lv, Gang Lu, Yuling Cai, Ruibao Su, Liang Liang, Xin Wang, Wenyu Mu, Xiuqing He, Tao Huang, Jinlong Ma, Yueran Zhao, Zi-Jiang Chen, Yuanchao Xue, Hongbin Liu, Wai-Yee Chan
2023, 14(1): 51-63. doi: 10.1093/procel/pwac040
RBM46 is a germ cell-specific RNA-binding protein required for gametogenesis, but the targets and molecular functions of RBM46 remain unknown. Here, we demonstrate that RBM46 binds at specific motifs in the 3'UTRs of mRNAs encoding multiple meiotic cohesin subunits and show that RBM46 is required for normal synaptonemal complex formation during meiosis initiation. Using a recently reported, high-resolution technique known as LACE-seq and working with low-input cells, we profiled the targets of RBM46 at single-nucleotide resolution in leptotene and zygotene stage gametes. We found that RBM46 preferentially binds target mRNAs containing GCCUAU/GUUCGA motifs in their 3'UTRs regions. In Rbm46 knockout mice, the RBM46-target cohesin subunits displayed unaltered mRNA levels but had reduced translation, resulting in the failed assembly of axial elements, synapsis disruption, and meiotic arrest. Our study thus provides mechanistic insights into the molecular functions of RBM46 in gametogenesis and illustrates the power of LACE-seq for investigations of RNA-binding protein functions when working with low-abundance input materials.
A CRISPR activation screen identifies genes that enhance SARS-CoV-2 infection
Fei Feng, Yunkai Zhu, Yanlong Ma, Yuyan Wang, Yin Yu, Xinran Sun, Yuanlin Song, Zhugui Shao, Xinxin Huang, Ying Liao, Jingyun Ma, Yuping He, Mingyuan Wang, Longhai Tang, Yaowei Huang, Jincun Zhao, Qiang Ding, Youhua Xie, Qiliang Cai, Hui Xiao, Chun Li, Zhenghong Yuan, Rong Zhang
2023, 14(1): 64-68. doi: 10.1093/procel/pwac036
Single-dose AAV-based vaccine induces a high level of neutralizing antibodies against SARS-CoV-2 in rhesus macaques
Dali Tong, Mei Zhang, Yunru Yang, Han Xia, Haiyang Tong, Huajun Zhang, Weihong Zeng, Muziying Liu, Yan Wu, Huan Ma, Xue Hu, Weiyong Liu, Yuan Cai, Yanfeng Yao, Yichuan Yao, Kunpeng Liu, Shifang Shan, Yajuan Li, Ge Gao, Weiwei Guo, Yun Peng, Shaohong Chen, Juhong Rao, Jiaxuan Zhao, Juan Min, Qingjun Zhu, Yanmin Zheng, Lianxin Liu, Chao Shan, Kai Zhong, Zilong Qiu, Tengchuan Jin, Sandra Chiu, Zhiming Yuan, Tian Xue
2023, 14(1): 69-73. doi: 10.1093/procel/pwac020
A core epitope targeting antibody of SARS-CoV-2
Simeng Zhao, Fengjiang Liu, Shizhen Qiu, Qiaoshuai Lan, Yiran Wu, Wei Xu, Junzi Ke, Jie Yang, Xiaoyan Liu, Kun Wang, Hangtian Guo, Shuai Xia, Fangfang Zhang, Jiabei Wang, Xiaowen Hu, Lu Lu, Shibo Jiang, Suwen Zhao, Lianxin Liu, Youhua Xie, Xiuna Yang, Haopeng Wang, Guisheng Zhong
2023, 14(1): 74-78. doi: 10.1093/procel/pwac042