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De Novo Macrocyclic Peptide Inhibitors of Hepatitis B Virus Cellular Entry
Cell Chemical Biology ( IF 6.6 ) Pub Date : 2018-05-17 , DOI: 10.1016/j.chembiol.2018.04.011
Toby Passioura , Koichi Watashi , Kento Fukano , Satomi Shimura , Wakana Saso , Ryo Morishita , Yuki Ogasawara , Yasuhito Tanaka , Masashi Mizokami , Camille Sureau , Hiroaki Suga , Takaji Wakita

Hepatitis B virus (HBV) constitutes a significant public health burden, and currently available treatment options are not generally curative, necessitating the development of new therapeutics. Here we have applied random non-standard peptide integrated discovery (RaPID) screening to identify small macrocyclic peptide inhibitors of HBV entry that target the cell-surface receptor for HBV, sodium taurocholate cotransporting polypeptide (NTCP). In addition to their anti-HBV activity, these molecules also inhibit cellular entry by the related hepatitis D virus (HDV), and are active against diverse strains of HBV (including clinically relevant nucleos(t)ide analog-resistant and vaccine escaping strains). Importantly, these macrocyclic peptides, in contrast to other NTCP-binding HBV entry inhibitors, exhibited no inhibition of NTCP-mediated bile acid uptake, making them appealing candidates for therapeutic development.

中文翻译:

De Novo乙型肝炎病毒细胞进入的大环肽抑制剂

乙型肝炎病毒(HBV)构成了重大的公共卫生负担,当前可用的治疗方法通常无法治愈,因此需要开发新的治疗方法。在这里,我们应用了随机非标准肽整合发现(RaPID)筛选,以鉴定靶向HBV细胞表面受体牛磺胆酸钠共转运多肽(NTCP)的HBV进入的小大环肽抑制剂。这些分子除了具有抗HBV活性外,还抑制相关D型肝炎病毒(HDV)进入细胞,并且对各种HBV株具有活性(包括临床相关的对核苷酸(t)ide类似物具有抗药性和疫苗逃逸株)。 。重要的是,与其他结合NTCP的HBV进入抑制剂相比,这些大环肽
更新日期:2018-07-20
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