Scalable Synthesis, In Vitro cccDNA Reduction, and In Vivo Antihepatitis B Virus Activity of a Phosphonomethoxydeoxythreosyl Adenine Prodrug
Min Luo 1 , Shuo Wu 2 , Raj Kalkeri 3 , Roger G Ptak 3 , Tianlun Zhou 4 , Lieve Van Mellaert 5 , Chuanmin Wang 6 , Shrinivas G Dumbre 1 , Timothy Block 4 , Elisabetta Groaz 1 , Steven De Jonghe 7 , Yuhuan Li 2 , Piet Herdewijn 1
Affiliations
Affiliations
1
Medicinal Chemistry, KU Leuven, Rega Institute for Medical Research, Herestraat 49-box 1041, 3000 Leuven, Belgium.
2
CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 1, Tiantan Xili, 100050 Beijing, China.
3
Department of Infectious Disease Research, Southern Research Institute, 431 Aviation Way, Frederick, Maryland 21701, United States.
4
Baruch S. Blumberg Institute, Doylestown, Pennsylvania 18902, United States.
5
Department of Microbiology, Immunology and Transplantation, Laboratory of Molecular Bacteriology, KU Leuven, Rega Institute for Medical Research, Herestraat 49-box 1037, 3000 Leuven, Belgium.
6
Department of Infectious Diseases, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China.
7
Department of Microbiology, Immunology and Transplantation, Laboratory of Virology and Chemotherapy, KU Leuven, Rega Institute for Medical Research, Herestraat 49-box 1043, 3000 Leuven, Belgium.
PMID: 33191744 DOI: 10.1021/acs.jmedchem.0c01381
Abstract
Standard literature procedures for the chemical synthesis of l-threose nucleosides generally employ l-ascorbic acid as starting material. Herein, we have explored two alternative routes that start from either l-arabitol or l-diethyl tartrate, both affording 2-O-methyl-l-threofuranose as a key building block for nucleobase incorporation. The access to multigram quantities of this glycosyl donor in a reproducible fashion allows for the preparation of 2'-deoxy-α-l-threofuranosyl phosphonate nucleosides on a large scale. This methodology was applied to the gram scale synthesis of an aryloxy amidate prodrug of phosphonomethoxydeoxythreosyl adenine. This prodrug exerted potent activity against an entecavir-resistant hepatitis B virus (HBV) strain, while leading to a significant reduction in the levels of HBV covalently closed circular DNA in a cellular assay. Furthermore, its remarkable anti-HBV efficacy was also confirmed in vivo using a hydrodynamic injection-based HBV mouse model, without relevant toxicity and systemic exposure occurring. 作者: StephenW 时间: 2020-11-19 14:59