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| 1 | High-throughput screening identifies established drugs as SARS-CoV-2 PLpro inhibitors显示文摘A new coronavirus(SARS-CoV-2)has been identified as the etiologic agent for the COVID-19 outbreak.Currently,effective treatment options remain very limited for this disease;therefore,there is an urgent need to identify new anti-COVID-19 agents.In this study,we screened over 6,000 compounds that included approved drugs,drug candidates in clinical trials,and pharmacologically active compounds to identify leads that target the SARS-CoV-2 papain-like protease(PLpro).Together with main protease(Mpro),PLpro is responsible for processing the viral replicase polyprotein into functional units.There-fore,it is an attractive target for antiviral drug develop-ment.Here we discovered four compounds,YM155,cryptotanshinone,tanshinone I and GRL0617 that inhibit SARS-CoV-2 PLpro with IC50 values ranging from 1.39 to 5.63 pmol/L.These compounds also exhibit strong antiviral activities in cell-based assays.YM155,an anti-cancer drug candidate in clinical trials,has the most potent antiviral activity with an EC50 value of 170 nmol/L.In addition,we have determined the crystal structures of this enzyme and its complex with YM155,revealing a unique binding mode.YM155 simultaneously targets three'hot'spots on PLpro,including the substrate-binding pocket,the interferon stimulating gene product 15(ISG15)binding site and zinc finger motif.Our results demonstrate the efficacy of this screening and repur-posing strategy,which has led to the discovery of new drug leads with clinical potential for COVID-19 treatments. | Yao Zhao Xiaoyu Du Yinkai Duan Xiaoyan Pan Yifang Sun Tian You Lin Han Zhenming Jin Weijuan Shang Jing Yu Hangtian Guo Qianying Liu Yan Wu Chao Peng Jun Wang Chenghao Zhu Xiuna Yang Kailin Yang Ying Lei Luke W.Guddat Wenqing Xu Gengfu Xiao Lei Sun Leike Zhang Zihe Rao Haitao Yang | 2021 | Protein & Cell2021，12，11： | 4 |
| 2 | Cryo-EM snapshots of mycobacterial arabinosyltransferase complex EmbB2-AcpM2显示文摘Inhibition of Mycobacterium tuberculosis(Mtb)cell wall assembly is an established strategy for anti-TB chemotherapy.Arabinosyltransferase EmbB,which catalyzes the transfer of arabinose from the donor decaprenyl-phosphate-arabinose(DPA)to its arabinosyl acceptor is an essential enzyme for Mtb cell wall synthesis.Analysis of drug resistance mutations suggests that EmbB is the main target of the front-line anti-TB drug,ethambutol.Herein,we report the cryo-EM structures of Mycobacterium smegmatis EmbB in its'resting state'and DPA-bound'active state'.EmbB is a fifteen-transmembrane-spanning protein,assembled as a dimer.Each protomer has an associated acyl-carrier-protein(AcpM)on their cytoplasmic surface.Confor-mational changes upon DPA binding indicate an asym-metric movement within the EmbB dimer during catalysis.Functional studies have identified critical residues in substrate recognition and catalysis,and demonstrated that ethambutol inhibits transferase activity of EmbB by competing with DPA.The structures represent the first step directed towards a rational approach for anti-TB drug discovery. | Lu Zhang Yao Zha Ruogu Gao Jun Li Xiuna Yang Yan Gao Wei Zhao Sudagar S.Gurcha Natacha Veerapen Sarah M.Batt Kajelle Kaur Besra Wenqing Xu Lijun Bi Xian'en Zhang Luke W.Guddat Haitao Yang Quan Wang Gurdyal S.Besra Zihe Rao | 2020 | Protein & Cell2020，11，7： | 0 |
| 3 | Broad spectrum antibiotic-degrading metallo-β-lactamases are phylogenetically diverse显示文摘Dear Editor, Antibiotic resistance has emerged as a major threat to global health;multi-drug resistant bacteria already kill more patients in the United States each year than HIV/AIDS, Parkinson's disease, emphysema and homicide combined (Laxminarayan et al., 2013).Among the most effective bacterial resistance mechanisms are β-lactamases, a family of enzymes that are divided into four distinct classes.Classes A, C and D (serine-β-lactamases, SBLs) use a catalytic site serine residue to initiate inactivation of the antibiotic, while Class B (metallo-β-lactamases, MBLs) relies on a Zn2+-activated hydroxide (Walsh et al., 2005;Bush and Jacoby,2010;Mitic et al., 2014;Lisa et al., 2017).Clinically relevant inhibitors of Class C and D SBLs are available and in use (e.g., clavulanic acid (CA), Drawz et al., 2010), but for MBLs the search for such inhibitors has remained challenging (McGeary et al., 2017). | Marcelo Monteiro Pedroso David W.Waite Okke Melse Liam Wilson Natasa Mitic Ross P.McGeary Iris Antes Luke W.Guddat Philip Hugenholtz Gerhard Schenk | 2020 | Protein & Cell2020，11，8： | 0 |
| 4 | Cryo-EM structures of a prokaryotic heme transporter CvdDC显示文摘DearEditor,Heme is an essential cofactor required across all kingdoms of life utilized in numerous biological processes,including cellular respiration.CydDC is a prokaryotic ATP-binding cassette(ABC)transporter required for heme assembling in respiratory cytochrome bd oxidase(Georgiou et al.,1987;Poole et al.,1989),a promising target for drug discovery(Borisov et al.,2011).CydDC is thought to play a role in maintaining an optimum periplasmic redox poise that is required for the incorporation of heme cofactors(Yamashita et al.,2014).It also suggested that CydDC is involved in heme processing by mediating glutathione/cysteine translocation(Cook and Poole,2000;Cook et al.,2002),although a role in heme translocation seems unlikely(Yamashita et al.,2014).To date,CydDC has been shown to be important for disulfide bond formation,motility,respiration,and tolerance to nitric oxide and antibiotics(Poole et al.,2019). | Chen Zhu Yanfeng Shi Jing Yu Wenhao Zhao Lingqiao Li Jingxi Liang Xiaolin Yang Bing Zhang Yao Zhao Yan Gao Xiaobo Chen Xiuna Yang Lu Zhang Luke W.Guddat Lei Liu Haitao Yang Zihe Rao Jun Li | 2023 | Protein & Cell2023，14，12： | 0 |
| 5 | HERBICIDES THAT INHIBIT ACETOLACTATE SYNTHASE显示文摘1 INTRODUCTION Herbicides are an essential pillar in modern agricultural practice.They are used to selectively reduce the growth of weeds in crops and natural environments.Early weed mitigating chemicals date back to Roman times and include substances as simple as table salt,sulfuric acid and carbon bisulfide.However,these were non-selective,required high application rates and could be toxic not only to the target weeds but to other plants and to animals.The first major advance in the development of tailored herbicides began in the mid 1940s with the development of the first organic growth regulators such as 2,4 dichlorophenoxyacetic acid(2,4-D)[1].The next major advance came in the 1970s with the discovery of glyphosate[2],marketed as Roundup,a herbicide that is routinely used to eradicate broad leaf weeds and grasses. | Thierry LONHIENNE Mario Daniel GARCIA Yu Shang LOW Luke W.GUDDAT | 2022 | Frontiers of Agricultural Science and Engineering2022，9，1： | 0 |
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