Natural Apocarotenoids and Their Synthetic Glycopeptide Conjugates Inhibit SARS-CoV-2 Replication

Area of Science:

• Drug discovery and development
• Virology
• Medicinal chemistry

Background:

• The COVID-19 pandemic necessitates novel antiviral therapies against SARS-CoV-2.
• Teicoplanin, a glycopeptide antibiotic, shows potential antiviral properties, enhanced by lipophilic modifications.

Purpose of the Study:

• To synthesize and evaluate novel lipophilic apocarotenoid conjugates of teicoplanin and related compounds for SARS-CoV-2 inhibition.
• To investigate the antiviral mechanisms of these conjugates and parent compounds.

Main Methods:

• Synthesis of teicoplanin, pseudoaglycone, and ristocetin aglycone apocarotenoid conjugates.
• Antiviral testing in Vero E6 cells using cell viability assays and quantitative PCR for viral RNA.
• Mechanistic studies involving cathepsin L, cathepsin B, and 3CLPro, supported by computational analysis.

Main Results:

• Several synthesized conjugates exhibited micromolar inhibitory activity against SARS-CoV-2 replication.
• Bixin and β-apo-8'carotenoic acid demonstrated significant anti-SARS-CoV-2 effects.
• Conjugates displayed dual inhibitory actions, while apocarotenoids primarily targeted cathepsin B and L.

Conclusions:

• Teicoplanin conjugates and natural apocarotenoids like bixin represent promising candidates for further development as SARS-CoV-2 antivirals.
• The availability and established safety profiles of teicoplanin and bixin warrant their continued investigation for antiviral applications.