Reshaping an Acyclic Nucleoside Phosphonate into a Selective Anti-hepatitis B Virus Compound

Area of Science:

• Medicinal Chemistry
• Virology
• Organic Synthesis

Background:

• Acyclic nucleoside phosphonates are crucial antiviral agents.
• Structural modifications can alter antiviral selectivity and potency.
• Hepatitis B virus (HBV) remains a significant global health concern requiring novel therapeutics.

Purpose of the Study:

• To investigate the impact of acyclic chain 2-substitution on the antiviral spectrum of HPMP nucleotides.
• To identify novel anti-HBV agents with improved potency and selectivity.
• To develop a promising drug candidate for HBV treatment.

Main Methods:

• Synthesis of racemic MHPMP and EHPMP nucleotide series.
• Antiviral activity screening against HBV.
• Sharpless asymmetric epoxidation for enantioseparation.
• Potency and selectivity evaluation of enantiomers and prodrugs.

Main Results:

• Guanine derivatives of MHPMP and EHPMP showed submicromolar anti-HBV activity.
• (S)-enantiomers were 8-26 fold more potent than (R)-enantiomers.
• (S)-EHPMPG prodrug demonstrated high potency (EC50 = 9.27 nM) and selectivity (SI50 > 10,787).

Conclusions:

• Nonpolar 2-substitution redirects HPMP nucleotide selectivity towards HBV.
• Enantiomeric configuration significantly impacts anti-HBV potency.
• (S)-EHPMPG prodrug is a highly promising candidate for further anti-HBV drug development.