**3. Known Metabolites Produced by** *Cordyceps* **Fungi**

Different compounds have been isolated from entomopathogenic fungi including *Cordyceps* species [17]. One of the most important but arguable metabolites produced by *C. militaris* is cordycepin, i.e., the adenosine analog 3'-deoxyadenosine (Figure 2). This compound is not produced in *O. sinensis* and *C. cicadae;* elucidation of its biosynthetic mechanism showed that the responsible BGC is only present in *C. militaris* and *C. kyusyuensis* as well as the evolutionarily distant mold fungus *Aspergillus nidulans* [19]. It was later found that the field-collected samples of *O. sinensis*, i.e., the complex of fruiting body and insect cadaver, were frequently contaminated with *A. nidulans* and even *C. militaris* that might contribute to the detection of trace amounts of cordycepin in caterpillar fungus [30]. Cordycepin can inhibit RNA synthesis and has demonstrated immense medicinal potential (Table 1), including anti-cancer, anti-inflammatory, antibiotic, anti-virus, and antioxidant activities [31]. However, in addition to its dosage-dependent toxicity to different cells, cordycepin has shown an effect in stimulating testosterone production in the models of both mouse Ledydig cells and mice, which may alter male fertility [32]. Recently, it has been shown that the anti-leukemia drug pentostatin (Figure 2), i.e., the 2'-deoxycoformycin originally isolated from *Streptomyces antibioticus* being an irreversible inhibitor of adenosine deaminase, can also be produced by *C. militaris* through the same BGC for cordycepin production via a protector–protégé strategy [19]. Similar to other chemotherapeutic drugs/agents, dosage- and schedule-dependent side effects have also been observed for pentostatin that include nausea, diarrhea, and renal and neurological toxicities [33]. The test of cordycepin in combination with pentostatin can trigger severe gastrointestinal toxicity and bone marrow toxicity in dogs [34].

**Figure 2.** Structure of the selected metabolites identified from *Cordyceps* fungi.

Apart from cordycepin and pentostatin, another adenosine analog *N*6-(2-Hydroxyethyl)-adenosine (HEA) has been identified in *C. cicadae*, *C. militaris*, and other species of *Cordyceps* with renal protection and anti-cancer activities [35,36]. Insecticidal activity of HEA has also been demonstrated by targeting the adenosine receptor (AdoR) of insects [37], suggesting that adenosine analogs can be recognized by AdoR(s) [38]. A different family of AdoRs, the G-protein coupled receptors with seven transmembrane domains, has been identified in humans as potential drug targets [39]. Since adenosine is multifunctional in the physiology of different organisms, the functions of cordycepin and HEA are still unclear, notably whether they act as agonists or antagonists of AdoRs in mammals. Deletion of *AdoRa1* in mice has led to decreased fertility and an increased risk of seizures [38]. The long-term effect of *Cordyceps* consumption and the effects of cordycepin and HEA administration on activation or inactivation of AdoRs require further investigation.

Other known metabolites produced by either *C. militaris* or *C. cicadae* include 2-pyridone alkaloid tenellin-like compounds and the bibenzoquinone oosporein (Figure 2). Different structures of Tenellin-like pyridones have been identified in different Cordycipitaceae fungi including fumosorinone produced by *C.* (*Isaria*) *fumosorosea* [40], farinosones by *I. farinosus* [41], and militarinones by *C. militaris* [42]. These 2-pyridones (Table 1) can maintain iron hemostasis and have also shown profound neuritogenic activity and cell cytotoxicities [42]. Oosporein, originally identified from the insect pathogen *Beauveria bassiana* (Syn. *Cordyceps bassiana*), shows insecticidal and antibiotic activities that promote fungal infection of insect hosts [9,43]. The conserved gene cluster and production of oosporein has been detected in *C. cicadae* [23]. This compound can also cause gout in avian species including chickens, turkeys and other birds, and can therefore threaten the safety of the poultry industry if contaminated substrates are used as feed [44].

A few cyclodepsipeptides (Figure 2) have also been identified from *Cordyceps* fungi, e.g., beauveriolide I and III from *C. militaris* [45] and beauvericin from *C. cicadae* [23,46]. Beauveriolides have demonstrated anti-aging [47], beta-amyloid-lowering [48], and anti-atherogenic activity by inhibition of lipid droplet accumulation in macrophages without any obvious side effects [49]. However, insecticidal and nematicidal beauvericin, first isolated from *B. bassiana*, can induce cytotoxicity and cell apoptosis in a dose-dependent manner due to its ionophoric property that can increase ion permeability in membranes [50]. Overall, along with the beneficial medicinal and or biological activities, different negative effects are also evident with the compounds identified from *Cordyceps* fungi that raise safety concerns about its consumption.
