Amide-containing α-hydroxytropolones as inhibitors of hepatitis B virus replication

Qilan Li; Elena Lomonosova; Maureen J Donlin; Feng Cao; Austin O'Dea; Brienna Milleson; Alex J Berkowitz; John-Charles Baucom; John P Stasiak; Daniel V Schiavone; Rudolf G Abdelmessih; Anastasiya Lyubimova; Americo J Fraboni; Lauren P Bejcek; Juan A Villa; Emilio Gallicchio; Ryan P Murelli; John E Tavis

doi:10.1016/j.antiviral.2020.104777

Amide-containing α-hydroxytropolones as inhibitors of hepatitis B virus replication

Antiviral Res. 2020 May:177:104777. doi: 10.1016/j.antiviral.2020.104777. Epub 2020 Mar 23.

Authors

Qilan Li¹, Elena Lomonosova², Maureen J Donlin³, Feng Cao⁴, Austin O'Dea⁵, Brienna Milleson¹, Alex J Berkowitz⁶, John-Charles Baucom⁷, John P Stasiak⁸, Daniel V Schiavone⁹, Rudolf G Abdelmessih¹⁰, Anastasiya Lyubimova¹¹, Americo J Fraboni¹², Lauren P Bejcek¹³, Juan A Villa¹⁴, Emilio Gallicchio¹⁵, Ryan P Murelli¹⁶, John E Tavis¹⁷

Affiliations

¹ Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, 1100 S. Grand Blvd, Saint Louis, MO, 63104, USA.
² Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, 1100 S. Grand Blvd, Saint Louis, MO, 63104, USA. Electronic address: lomonosova.elena@wustl.edu.
³ Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, 1100 S. Grand Blvd, Saint Louis, MO, 63104, USA. Electronic address: maureen.donlin@health.slu.edu.
⁴ John Cochran Division, Department of Veterans Affairs Medical Center, Saint Louis, MO, USA. Electronic address: feng.cao@va.gov.
⁵ Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, 1100 S. Grand Blvd, Saint Louis, MO, 63104, USA. Electronic address: austin.odea@health.slu.edu.
⁶ Department of Chemistry, Brooklyn College, The City University of New York, Brooklyn, NY, 11210, USA; Program in Chemistry, The Graduate Center of The City University of New York, New York, NY, 11210, USA. Electronic address: aberkowitz@gradcenter.cuny.edu.
⁷ Department of Chemistry, Brooklyn College, The City University of New York, Brooklyn, NY, 11210, USA; Program in Chemistry, The Graduate Center of The City University of New York, New York, NY, 11210, USA. Electronic address: jbaucom@gradcenter.cuny.edu.
⁸ Department of Chemistry, Brooklyn College, The City University of New York, Brooklyn, NY, 11210, USA. Electronic address: j.stasiak@aol.com.
⁹ Department of Chemistry, Brooklyn College, The City University of New York, Brooklyn, NY, 11210, USA; Program in Chemistry, The Graduate Center of The City University of New York, New York, NY, 11210, USA. Electronic address: Daniel.Schiavone@brooklyn.cuny.edu.
¹⁰ Department of Chemistry, Brooklyn College, The City University of New York, Brooklyn, NY, 11210, USA. Electronic address: rudolf117@live.com.
¹¹ Department of Chemistry, Brooklyn College, The City University of New York, Brooklyn, NY, 11210, USA. Electronic address: anastasialok@hotmail.com.
¹² Department of Chemistry, Brooklyn College, The City University of New York, Brooklyn, NY, 11210, USA. Electronic address: frabonia@gmail.com.
¹³ Department of Chemistry, Brooklyn College, The City University of New York, Brooklyn, NY, 11210, USA; Program in Chemistry, The Graduate Center of The City University of New York, New York, NY, 11210, USA. Electronic address: Lauren.Bejcek@brooklyn.cuny.edu.
¹⁴ Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, 1100 S. Grand Blvd, Saint Louis, MO, 63104, USA. Electronic address: juanvillatorrecilla@wustl.edu.
¹⁵ Department of Chemistry, Brooklyn College, The City University of New York, Brooklyn, NY, 11210, USA; Program in Chemistry, The Graduate Center of The City University of New York, New York, NY, 11210, USA; Program in Biochemistry, The Graduate Center of The City University of New York, New York, NY, 11210, USA. Electronic address: egallicchio@brooklyn.cuny.edu.
¹⁶ Department of Chemistry, Brooklyn College, The City University of New York, Brooklyn, NY, 11210, USA; Program in Chemistry, The Graduate Center of The City University of New York, New York, NY, 11210, USA; Program in Biochemistry, The Graduate Center of The City University of New York, New York, NY, 11210, USA. Electronic address: rpmurelli@brooklyn.cuny.edu.
¹⁷ Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, 1100 S. Grand Blvd, Saint Louis, MO, 63104, USA. Electronic address: john.tavis@health.slu.edu.

Abstract

The Hepatitis B Virus (HBV) ribonuclease H (RNaseH) is a promising but unexploited drug target. Here, we synthesized and analyzed a library of 57 amide-containing α-hydroxytropolones (αHTs) as potential leads for HBV drug development. Fifty percent effective concentrations ranged from 0.31 to 54 μM, with selectivity indexes in cell culture of up to 80. Activity against the HBV RNaseH was confirmed in semi-quantitative enzymatic assays with recombinant HBV RNaseH. The compounds were overall poorly active against human ribonuclease H1, with 50% inhibitory concentrations of 5.1 to >1,000 μM. The αHTs had modest activity against growth of the fungal pathogen Cryptococcus neoformans, but had very limited activity against growth of the Gram - bacterium Escherichia coli and the Gram + bacterium Staphylococcus aureus, indicating substantial selectivity for HBV. A molecular model of the HBV RNaseH templated against the Ty3 RNaseH was generated. Docking the compounds to the RNaseH revealed the anticipated binding pose with the divalent cation coordinating motif on the compounds chelating the two Mn⁺⁺ ions modeled into the active site. These studies reveal that that amide αHTs can be strong, specific HBV inhibitors that merit further assessment toward becoming anti-HBV drugs.

Keywords: Hepatitis B Virus; Molecular modeling; Ribonuclease H; α-Hydroxytropolones.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Amides / chemistry
Amides / pharmacology*
Antiviral Agents / chemistry
Antiviral Agents / pharmacology*
Cell Line
Drug Discovery
Hepatitis B / drug therapy
Hepatitis B virus / drug effects*
Hepatitis B virus / physiology
Humans
Models, Molecular
Tropolone / chemical synthesis
Tropolone / chemistry
Tropolone / pharmacology*
Virus Replication / drug effects*

Substances

Amides
Antiviral Agents
Tropolone

Abstract

Publication types

MeSH terms

Substances

Grants and funding