Structure-activity relationship study of itraconazole, a broad-range inhibitor of picornavirus replication that...

Area of Science:

• Pharmacology
• Drug Discovery
• Molecular Biology

Background:

• Itraconazole (ITZ), an FDA-approved antifungal, exhibits anticancer properties via VEGFR2, mTOR, and Hedgehog signaling pathways.
• Recent findings reveal ITZ possesses broad-spectrum antiviral activity against various viruses, mediated by oxysterol-binding protein (OSBP).
• This antiviral mechanism is independent of ITZ's known antifungal and anticancer activities.

Purpose of the Study:

• To identify the structural features of ITZ essential for its OSBP-mediated antiviral activity.
• To compare these features with those required for ITZ's other pharmacological actions.
• To explore the binding interaction between ITZ and OSBP using in silico methods.

Main Methods:

• Structure-activity relationship analysis of ITZ variants.
• Comparison with published data on ITZ's effects on VEGFR2 and Hedgehog signaling.
• In silico molecular docking studies to predict ITZ-OSBP binding.

Main Results:

• The five-ring backbone and sec-butyl chain of ITZ are critical for antiviral activity against OSBP.
• The triazole moiety, essential for antifungal effects, is not required for antiviral activity.
• Structural requirements for OSBP-mediated antiviral activity largely overlap with those for VEGFR2 trafficking inhibition, but not Hedgehog signaling.
• In silico studies provided insights into potential ITZ binding modes within OSBP.

Conclusions:

• Pharmacological activities of ITZ can be dissociated, highlighting its versatile mechanisms.
• The distinct structural requirements for antiviral activity offer a basis for developing specific ITZ-based antiviral agents.
• This research supports the development of novel antiviral therapies with reduced off-target effects.