摘要：Beta-ketoacyl-acyl-carrier-protein synthase Ⅱ,an important enzyme in biosynthesis of bacterial fatty acid,is an attractive target in antibacterial drug design. Platensimycin(PTM), produced by Streptomyces platensis, has a strong, broad-spectrum Gram-positive antibacterial activity by selectively targeting to Fab F but exhibits no inhibition to the Fab F from Streptomyces platensis(spFabF). To study the self-resistance mechanism within the PTM-producing strain and provide hint for development of novel antibiotics, it is imperative to solve the structure of spFabF and elucidate the difference between spFabF and other Fab Fs which are not resistant to PTM. To this end, we constructed four chimeric Fab Fs based on the sequence of spFabF and its homologous protein after the expression of wide-type spFabF was failed. The crystal structure of one chimera, js_(200)FabF, of 91.2% sequence identity to spFabF,was solved. A structure comparison of js_(200)FabF with a PTM-bound Fab F suggested that three loops nearby the catalytic site might play key roles in preventing the binding of PTM to spFabF. The results provide an encouraging basis for further studies on the self-resistance mechanismand structure-based design of novel antibiotics targeting FabFs.

摘要：Proprotein convertase subtilisin/kexin type 9(PCSK9)modulators may attenuate PCSK9-induced low-density lipoprotein receptor(LDLR)degradation in lysosome and promote the clearance of circulating low-density lipoprotein cholesterol(LDL-C).A novel series of tetrahydroprotoberberine derivatives(THPBs)were designed,synthesized,and evaluated as PCSK9 modulators for the treatment of *** them,eight compounds exhibited excellent activities in downregulatinghepatic PCSK9 expression better than berberine in HepG2 *** addition,five compounds 15,18,22,(R)-22,and(S)-22 showed better performance in the low-density lipoprotein,labeled with 1,1’-dioctadecyl-3,3,3’,3’-tetramethyl-indocarbocyanine perchlorate(Dil-LDL)uptake assay,compared with berberine at the same *** 22,selected for in vivo evaluation,demonstrated significant reductions of total cholesterol(TC)and LDL-C in hyperlipidemic hamsters with a good pharmacokinetic *** exploring of the lipid-lowering mechanism showed that compound 22 promoted hepatic LDLR expression in a dose-dependent manner in HepG2 *** results of human ether-ago-go related gene(hERG)inhibition assay indicated the potential druggability for compound 22,which is a promising lead compound for the development of PCSK9 modulator for the treatment of hyperlipidemia.

摘要：GPR40 has emerged as an attractive drug target for the treatment of type 2 diabetes due to its role in the enhancement of insulin secretion with glucose dependency. With the aim to improve the metabolic and safety profiles, a series of novel phenylpropionic acid derivatives were synthesized. Extensive structural optimization led to identification of compounds 22 g and 23 e as potent GPR40 agonists with moderate liver microsomal stability. All the discovery supported further exploration surrounding this scaffold.

摘要：Summary of main observation and conclusion To combat multidrug-resistant Gram-positive bacteria,new antimicrobials particularly those with novel mechanism of action are badly *** with conventional antibiotics which are typical inhibitors,small-molecule activators of bacterial CIpP represent a new class of *** ClpP activator has been developed for clinical ***,we conducted a screening on our library of benga-mide-like ring opened analogues and found that L472-2 possesses a low minimum inhibitory concentration(MIC)against *** and shows no activity for ClpP activation in vitro,but it displayed reduced antibacterial activity against *** with clpP *** order to obtain bengamide analogues that activate ClpP in vitro as well as possess antibacterial activity,we perform further structural modifications starting from *** 37 re-mains the antimicrobial activity and activation of ClpP protein in vitro,which could be viewed as a new chemical scaffold for ClpP activators and worthy of further investigation.

摘要：Nucleocapsid(N) protein plays crucial roles in the life cycle of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2), including the formation of ribonucleoprotein(RNP) complex with the viral *** we reported the crystal structures of the N-terminal domain(NTD) and C-terminal domain(CTD) of the N protein and an NTD-RNA complex. Our structures reveal a unique tetramer organization of NTD and identify a distinct RNA binding mode in the NTD-RNA complex, which could contribute to the formation of the RNP complex. We also screened small molecule inhibitors of N-NTD and N-CTD and discovered that ceftriaxone sodium, an antibiotic, can block the binding of RNA to NTD and inhibit the formation of the RNP complex. These results together could facilitate the further research of antiviral drug design targeting N protein.