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GAO Qianqian, HAN Kailin, WANG Guocheng, LU Tao. Advances in core protein allosteric modulators[J]. Journal of China Pharmaceutical University, 2019, 50(5): 516-522. DOI: 10.11665/j.issn.1000-5048.20190502
Citation: GAO Qianqian, HAN Kailin, WANG Guocheng, LU Tao. Advances in core protein allosteric modulators[J]. Journal of China Pharmaceutical University, 2019, 50(5): 516-522. DOI: 10.11665/j.issn.1000-5048.20190502
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Advances in core protein allosteric modulators

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    • Abstract
  • The core protein allosteric modulator targets the core protein and inhibits hepatitis B virus(HBV)replication by regulating the formation of covalently closed circular DNA(cccDNA), which is expected to completely cure hepatitis B and overcome the drug resistance of nucleoside drugs. This paper reviews the replication process of HBV, the function of core proteins, the mechanism, classification and research progress of core protein allosteric modulators, lists 12 drugs, and summarizes their mechanisms, categories, chemical structures, safety, anti-HBV effects, combined drug use, etc. In addition, the advantages and problems of core protein allosteric modulators are discussed to provide references for the development of new anti-HBV drugs.
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  • [1]
    Mak LY,Wong KH,Seto WK,et al.Hepatitis B core protein as a therapeutic target[J].Expert Opin Ther Targets,2017,21(12):1153-1159.
    [2]
    Razavi-Shearer D,Gamkrelidze I,Nguyen MH,et al.Global prevalence,treatment,and prevention of hepatitis B virus infection in 2016:a modelling study[J].Lancet Gastroenterol Hepatol,2018,3(6):383-403.
    [3]
    Jia JD,Zhuang H.Working together to promote access to chronic hepatitis B in China[J].Chin Hepatol(肝脏),2016,21(4):613-614.
    [4]
    Yan H,Zhong G,Xu G,et al.Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus[J].Elife,2012,13(1):e00049.
    [5]
    Pei Y,Wang C,Yan SF,et al.Past,Current,and future developments of therapeutic agents for treatment of chronic hepatitis B virus infection[J].J Med Chem,2017,60(15):6766-6767.
    [6]
    Chang J,Guo F,Zhao X,et al.Therapeutic strategies for a functional cure of chronic hepatitis B virus infection[J].Acta Pharm Sin B(药学学报),2014,4(4):248-257.
    [7]
    Zhu Y,Yamamoto T,Cullen J,et al.Kinetics of hepadnavirus loss from the liver during inhibition of viral DNA synthesis[J].J Virol,2001,75(1):311-322.
    [8]
    Lucifora J,Protzer U.Attacking hepatitis B virus cccDNA-The holy grail to hepatitis B cure[J].J Hepatol,2016,64(1):S41-S48.
    [9]
    Diab A,Foca A,Zoulim F,et al.The diverse functions of the hepatitis B core/capsid protein(HBc)in the viral life cycle:implications for the development of HBc-targeting antivirals[J].Antiviral Res,2018,149:211-220.
    [10]
    Wu S,Luo Y,Viswanathan U,et al.CpAMs induce assembly of HBV capsids with altered electrophoresis mobility:Implications for mechanism of inhibiting pgRNA packaging[J].Antiviral Res,2018,159:1-12.
    [11]
    Zhou Z, Hu T, Zhou X, et al. Heteroaryldihydropyrimidine(HAP)and sulfamoylbenzamide(SBA)inhibit hepatitis B virus replication by different molecular mechanisms[J].Sci Rep,2017,7(1):42374.
    [12]
    Wu S,Zhao Q,Zhang P,et al.Discovery and mechanistic study of benzamide derivatives that modulate hepatitis B virus capsid assembly[J].J Virol,2017,91(16):e00519-17.
    [13]
    Katen SP,Chirapu SR,Finn MG,et al.Trapping of hepatitis B virus capsid assembly intermediates by phenylpropenamide assembly accelerators[J].ACS Chem Biol,2010,5(12):1125-1136.
    [14]
    Ren Q,Liu X,Luo Z,et al.Discovery of hepatitis B virus capsid assembly inhibitors leading to a heteroaryldihydropyrimidine based clinical candidate(GLS4)[J].Bioorg Med Chem,2017,25(3):1042-1056.
    [15]
    Wang JH,Jiang D,Zhang YJ,et al.Heteroaryldihydropyrimidine compound GLS4 regulates both assembly and disassembly of HBV capsids to inhibit cccDNA formation[J].Hepatology,2017,66(S1):501-502.
    [16]
    Wu G,Liu B,Zhang Y,et al.Preclinical characterization of GLS4,an inhibitor of hepatitis B virus core particle assembly[J].Antimicrob Agents Chemother,2013,57(11):5344-5354.
    [17]
    Zhang H,Zhu XX,Chen H,et al.Safety,pharmacokinetics and anti-viral efficacy of novel core protein allosteric modifier GLS4 in patients with chronic hepatitis B:interim results from a 48 weeks phase 2a study[J].Hepatology,2018,68(6):1454-1455.
    [18]
    Yuen R,Agarwal K,Gane E,et al.Interim safety,tolerability pharmacokinetics,and antiviral activity of ABI-H0731,a novel core protein allosteric modulator,in healthy volunteers and non-cirrhotic viremic subjects with chronic hepatitis B[J].J Hepatol,2018,68(1):S111.
    [19]
    Zoulim F,Yogaratnam JZ,Vandenbossche JJ,et al.Safety,pharmakokinetics and antiviral activity of novel capsid assembly modulator(CAM)JNJ-56136379(JNJ-6379)intreatment-naive chronic hepatitis B(CHB)patients without cirrhosis[J].J Hepatol,2018,68(1):S102.
    [20]
    Zoulim F,Yogaratnam JZ,Vandenbossche JJ,et al.Safety,tolerability,pharmacokinetics and antiviral activity of JNJ-56136379,a novel HBV capsid assembly modulator,in non-cirrhotic,treatment-naïve subjects with chronic hepatitis B[J].Hepatology,2017,66(6):1263-1264.
    [21]
    Lam AM,Espiritu C,Vogel R,et al.Preclinical characterization of NVR 3-778,a first-in-class capsid assembly modulator against the hepatitis B virus[J].Antimicrob Agents Chemother,2018,63(1):e01734-18.
    [22]
    Yuen MF,Kim DJ,Weilert F,et al.NVR 3-778,a first-in-class HBV core inhibitor,alone and in combination with peg-interferon(PegIFN),in treatment-naive HBeAg-positive patients:early reductions in HBV DNA and HBeAg[J].J Hepatol,2016,64(2):S210-S211.
    [23]
    Lam A,Espiritu C,Flores O,et al.Effect of the combination of the HBV core inhibitor NVR 3-778 with nucleoside analogs or other HBV core inhibitors on the inhibition of HBV DNA replication in HepG2.2.15 cells[J].J Hepatol,2015,62(2):S559.
    [24]
    Paulsen D,Korolowicz KE,Bin L,et al.AIC649 in combination with entecavir leads to WHsAg loss in the woodchuck animal model of chronic hepatitis B[J].Hepatology,2017,66(6):1268.
    [25]
    Solveigh M.AiCuris reports positive phase 1 clinical trial results with immunomodulator AIC649 in patients with chronic hepatitis B[EB/OL].(2018-09-10)[2019-01-28] .https://www.biospace.com/article/aicuris-reports-positive-phase-1-clinical-trial-results-with-immunomodulator-aic649-in-patients-with-chronic-hepatitis-b.
    [26]
    Gane E,Liu A,Yuen ME,et al.RO7049389,a core protein allosteric modulator,demonstrates robust anti-HBV activity in chronic hepatitis B patients and is safe and well tolerated[J].J Hepatol,2018,68(1):S101.
    [27]
    Mani N,Cole AG,Phelps JR,et al.Preclinical profile of AB-423,an inhibitor of Hepatitis B virus pgRNA encapsidation[J].Antimicrob Agents Chemother,2018,62(6):e00082-18.
    [28]
    Mani N,Cole AG,Phelps JR,et al.In vitro and in vivo antiviral activities of AB-423 a potent small molecule inhibitor of hepatitis B virus capsid assembly[J].J Hepatol,2016,64(2):S392-S393.
    [29]
    Mani N,Li AHL,Ardzinski A,et al.Preclinical antiviral drug combination studies utilizing novel orally bioavailable investigational agents for chronic hepatitis B infection:AB-506,a next generation HBV capsid inhibitor,and AB-452,a HBV RNA destabilizer[J].J Hepatol,2018,68(1):S17.
    [30]
    Gane E,Schwabe C,Evanhcik M,et al.Phase 1a study of the safety,tolerability and pharmacokinetics of ABI-H2158,a novel second-generation HBV core inhibitor,in healthy volunteers[J].J Hepatol,2019,70(1):e146-e147.
    [31]
    Vaine M, Clugston S, Kass J, et al. Discovery of a novel core inhibitor EP-027367 with potent antiviral activity both in vitro and in a humanized mouse model[J].J Hepatol,2018,68(1):S19.
    [32]
    Bassit L,Cox B,Verma K,et al.Novel and potent HBV capsid modulator reduces HBeAg and cccDNA in core site directed T109I mutant in HepNTCP cells[J].J Hepatol,2018,68(1):S16-S17.
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