2020•Research SquareOpen access
A polypeptide D-TTK001 targeting HBx controls cccDNA against HBV
Xiaodong Zhang, Xiaodong Zhang, Hongfeng Yuan, Shuai Zhang, Shuqin Zhang, Lina Zhao, Hongwei Gao, Guang Yang, Xuezhi Zhang, Xuezhi Zhang, Haolin Yun, Changliang Shan, Yunxia Liu, Yu Geng, Wei Zheng, Xiuzhu Gao, Xiaomei Wang, Ying Yuan, Zhenchuan Miao, Ming Yin, Man Zhao, Yufei Wang, Jiapei Wang, Junqi Niu
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Abstract
Abstract Chronic infection of HBV is a serious global health issue. However, the HBV covalently closed circular DNA (cccDNA) cannot be completely cleaned in liver. Here, we engineer a novel polypeptide, termed D-TTK001, targeting HBV X protein (HBx) against HBV cccDNA. D-TTK001 is a D-type polypeptide, which has a high binding affinity to HBx. Interestingly, it is able to against HBV efficiently in primary human hepatocytes (PHHs) from three donors. D-TTK001 displays high activities against HBV, remarkably reducing the levels of cccDNA in the HBV-infected human liver-chimeric mice. Mechanically, D-TTK001 depresses cccDNA transcription by regulating the epigenetic modification of cccDNA minichromosome and disturbing the interaction of HBx with DDB1 in the cells. D-TTK001 decreases the levels of cccDNA by down-regulating MSL2, leading to the increase of APOBEC3B in liver. When combined with entecavir or interferon-α, D-TTK001 shows additive antiviral effects. Clinically, D-TTK001 is a strong candidate to clear cccDNA against HBV.
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