Back to Search
Start Over
CMCdG, a Novel Nucleoside Analog with Favorable Safety Features, Exerts Potent Activity against Wild-Type and Entecavir-Resistant Hepatitis B Virus.
- Source :
-
Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2019 Mar 27; Vol. 63 (4). Date of Electronic Publication: 2019 Mar 27 (Print Publication: 2019). - Publication Year :
- 2019
-
Abstract
- We designed, synthesized, and characterized a novel nucleoside analog, (1 S ,3 S ,5 S )-3-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-5-hydroxy-1-(hydroxymethyl)-2-methylene-cyclopentanecarbonitrile, or 4'-cyano-methylenecarbocyclic-2'-deoxyguanosine (CMCdG), and evaluated its anti-hepatitis B virus (anti-HBV) activity, safety, and related features. CMCdG's in vitro activity was determined using quantitative PCR and Southern blotting assays, and its cytotoxicity was determined with a 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay, while its in vivo activity and safety were determined in human liver-chimeric mice infected with wild-type HBV genotype Ce (HBV <subscript>WT</subscript> <superscript>Ce</superscript> ) and an entecavir (ETV)-resistant HBV variant containing the amino acid substitutions L180M, S202G, and M204V (HBV <subscript>ETV-R</subscript> <superscript>L180M/S202G/M204V</superscript> ). CMCdG potently inhibited HBV production in HepG2.2.15 cells (50% inhibitory concentration [IC <subscript>50</subscript> ], ∼30 nM) and HBV <subscript>WT</subscript> <superscript>Ce</superscript> plasmid-transfected Huh7 cells (IC <subscript>50</subscript> , 206 nM) and efficiently suppressed ETV-resistant HBV <subscript>ETV-R</subscript> <superscript>L180M/S202G/M204V</superscript> (IC <subscript>50</subscript> , 2,657 nM), while it showed no or little cytotoxicity (50% cytotoxic concentration, >500 μM in most hepatocytic cells examined). Two-week peroral administration of CMCdG (1 mg/kg of body weight/day once a day [q.d.]) to HBV <subscript>WT</subscript> <superscript>Ce</superscript> -infected human liver-chimeric mice reduced the level of viremia by ∼2 logs. CMCdG also reduced the level of HBV <subscript>ETV-R</subscript> <superscript>L180M/S202G/M204V</superscript> viremia by ∼1 log in HBV <subscript>ETV-R</subscript> <superscript>L180M/S202G/M204V</superscript> -infected human liver-chimeric mice, while ETV (1 mg/kg/day q.d.) completely failed to reduce the viremia. None of the CMCdG-treated mice had significant drug-related changes in body weights or serum human albumin levels. Structural analyses using homology modeling, semiempirical quantum methods, and molecular dynamics revealed that although ETV triphosphate (TP) forms good van der Waals contacts with L180 and M204 of HBV <subscript>WT</subscript> <superscript>Ce</superscript> reverse transcriptase (RT), its contacts with the M180 substitution are totally lost in the HBV <subscript>ETV-R</subscript> <superscript>L180M/S202G/M204V</superscript> RT complex. However, CMCdG-TP retains good contacts with both the HBV <subscript>WT</subscript> <superscript>Ce</superscript> RT and HBV <subscript>ETV-R</subscript> <superscript>L180M/S202G/M204V</superscript> RT complexes. The present data warrant further studies toward the development of CMCdG as a potential therapeutic for patients infected with drug-resistant HBV and shed light on the further development of more potent and safer anti-HBV agents.<br /> (Copyright © 2019 American Society for Microbiology.)
- Subjects :
- Animals
Antiviral Agents adverse effects
Cell Line, Tumor
DNA Replication drug effects
Drug Discovery
Drug Resistance, Viral
Guanine analogs & derivatives
Guanine pharmacology
Hep G2 Cells
Humans
Mice
Nucleosides adverse effects
Purines adverse effects
Reverse Transcriptase Inhibitors adverse effects
Serum Albumin analysis
Antiviral Agents pharmacology
Hepatitis B drug therapy
Hepatitis B virus drug effects
Nucleosides pharmacology
Purines pharmacology
Reverse Transcriptase Inhibitors pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1098-6596
- Volume :
- 63
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Antimicrobial agents and chemotherapy
- Publication Type :
- Academic Journal
- Accession number :
- 30670420
- Full Text :
- https://doi.org/10.1128/AAC.02143-18