(−)-Anisomelic acid (Figure 1) is a macrocyclic cembranolide with a trans-fused α-methylene-γ- lactone motif, which effectively inhibits SARS-CoV-2 replication and viral-induced cytopathic effects with an EC50 of 1.1 and 4.3 μM, respectively. Challenge studies of SARS-CoV-2-infected K18-hACE2 mice showed that oral administration of anisomelic acid and subcutaneous dosing of remdesivir can both reduce the viral titers in the lung tissue at the same level.
To facilitate drug discovery, we have developed a semisynthetic approach to shorten the project timelines, and our semisynthesis is characterized by the use of the naturally enriched and commercially available (+)-costunolide as the starting material. The key steps in our synthesis are ozonolysis and ring-closing metathesis reactions, and anisomelic-acid could be achieved in five steps with a 27% overall yield (Nat. Sci. Rev. 2022, 9, nwac176). The developed chemistry provides opportunities for development of anisomelic-acid-based antiviral agents.
Building upon our success with anisomelic acid, a potent macrocyclic cembranolide with inhibitory effects against SARS-CoV-2, our current efforts are focused on advancing its semisynthetic derivatives for enhanced antiviral efficacy. Anisomelic acid, featuring a trans-fused α-methylene-γ-lactone motif, has demonstrated significant promise by effectively reducing viral titers in SARS-CoV-2-infected K18-hACE2 mice, comparable to standard antiviral treatments like remdesivir.
To expedite drug discovery timelines, we have pioneered a semisynthetic approach using naturally abundant (+)-costunolide as a starting material. Key synthetic steps involve ozonolysis and ring-closing metathesis reactions, achieving anisomelic acid in just five steps with an overall yield of 27% (Nat. Sci. Rev. 2022, 9, nwac176). This streamlined synthesis opens avenues for developing novel antiviral agents based on anisomelic acid.
Looking forward, our research aims to optimize and diversify the chemical space around anisomelic acid through further semisynthetic modifications. This includes exploring structural analogues to improve potency, selectivity, and pharmacokinetic profiles against SARS-CoV-2 and other viral pathogens. We are also committed to leveraging computational and medicinal chemistry approaches to design and screen derivatives with enhanced antiviral properties.
Additionally, our focus extends to understanding the molecular mechanisms underlying anisomelic acid's antiviral activity, facilitating the development of targeted therapies and elucidating its potential as a broad-spectrum antiviral agent.
