Paraisariamides: Cycloheptapeptide Toxins from Entomopathogenic Fungi (Paraisaria spp.) That Inhibit Total Protein...

Area of Science:

• Natural Product Chemistry
• Mycology
• Chemical Biology

Background:

• Insect-associated fungi, particularly the Ophiocordycipitaceae family, are known sources of bioactive peptidic natural products.
• The genus *Paraisaria* includes insect-pathogenic fungi, some of which may be unintentionally consumed via infected edible insects, raising toxicological concerns.

Purpose of the Study:

• To discover, isolate, and elucidate the structures of novel peptidic natural products from *Paraisaria* species.
• To investigate the biological activities, including cytotoxicity and protein synthesis inhibition, of the identified compounds.
• To determine the localization and potential role of these compounds within the host-pathogen interaction.

Main Methods:

• Isolation and structure elucidation of paraisariamides A-H using spectroscopic techniques.
• Total synthesis of selected paraisariamides to confirm structures and enable biological testing.
• In vitro assays to assess cell-type specific toxicity against human cancer cell lines.
• Biochemical assays to evaluate inhibition of mammalian protein synthesis.
• Molecular cartography to visualize compound distribution in infected host tissues.

Main Results:

• Eight new N-methylated cyclic heptapeptides, paraisariamides A-H (1-8), were isolated from *Paraisaria cascadensis* and *P. insignis*.
• Total synthesis confirmed the structures of paraisariamides 1 and 5-8.
• Paraisariamides A-H exhibited differential cytotoxicity against various human cancer cell lines.
• The most potent cytotoxic compounds, paraisariamides E-H (5-8), were found to rapidly inhibit mammalian protein synthesis.
• Molecular cartography localized these compounds to the fungal endosclerotium within parasitized beetle larvae.

Conclusions:

• The *Paraisaria* genus produces a diverse family of N-methylated cyclic heptapeptides with significant cytotoxic and protein synthesis inhibitory activities.
• These findings highlight the potential of insect-associated fungi as a source of novel bioactive natural products.
• The localization and mechanism of action suggest these compounds may play a role in host-pathogen interactions by disrupting host protein synthesis.