Novel Multifunctional Cannabidiol-Based Analogues with In Silico, In Vitro, and In Vivo Anti-SARS-CoV-2 Effect.

Area of Science:

• Medicinal Chemistry
• Virology
• Pharmacology

Background:

• COVID-19 caused millions of global deaths, necessitating the search for effective antiviral therapies.
• Identifying compounds with both in vitro and in vivo efficacy against SARS-CoV-2 is crucial.

Purpose of the Study:

• To evaluate the antiviral activity of terpene-N-acyl-aryl-hydrazone analogues PQM-243 and PQM-249 against SARS-CoV-2.
• To assess the inhibitory effects of these compounds on angiotensin-converting enzyme 2 (ACE2) and the interaction between ACE2 and the SARS-CoV-2 receptor-binding domain (RBD).
• To investigate the in vivo anti-inflammatory effects in a SARS-CoV-2-induced pulmonary pneumonia model.

Main Methods:

• In vitro antiviral assays against SARS-CoV-2 and ACE2 inhibition assays.
• LUMMIT kit used to evaluate the inhibition of ACE2-RBD protein interactions.
• In vivo study using a SARS-CoV-2-induced pulmonary pneumonia mouse model with oral administration of compounds.

Main Results:

• PQM-243 and PQM-249 demonstrated significant antiviral activity (IC50 values 0.0648 ± 0.041 µM and 0.2860 ± 0.057 µM) and high selectivity indices (>1543.21 and 349.65).
• Compounds effectively inhibited ACE2 (IC50 values 12.1 nM and 13.3 nM) and significantly reduced ACE2-RBD interactions.
• Oral administration of both compounds reduced SARS-CoV-2-induced lung inflammation in vivo, indicating a multi-target pharmacological profile.

Conclusions:

• PQM-243 and PQM-249 are potent direct-acting antiviral agents against SARS-CoV-2, inhibiting viral viability and host cell entry.
• These compounds exhibit a multi-target profile, reducing viral load and associated lung inflammation.
• PQM-243 and PQM-249 represent promising prototypes for developing novel drug candidates for SARS-CoV-2 and other respiratory viral diseases.