Cordyceps proteins: An uncharted frontier in therapeutic bioactive research

Cordyceps is of importance in Asian medicine. Research has focused on small molecules, but little attention was given to protein-based bioactive compounds from Cordyceps despite their therapeutic promise. This study highlights the current evidence on the five major classes of protein found in Cordyceps species: proteases, cordymin, lectins, superoxide dismutases (SOD) and ribosome inactivating proteins (RIPs). The pharmacological, biochemical, functional insights and the biological importance of these proteins were highlighted and the gaps that present constrains to their clinical use. Cordymin, a low molecular weight (10.9 kDa) antifungal peptide isolated from C. militaris, exhibits HIV-1 reverse transcriptase inhibitory and antiproliferative activity, yet its three-dimensional structure, detailed pharmacokinetic profile and molecular mechanism remain largely unknown. Proteases catalyse the hydrolysis of peptides and amino acids. Although proteases have shown promising potential as a thrombolytic agent, detailed studies of substrate specificity, catalytic mechanisms and inhibitor interactions are still lacking. While Cu/Zn-SOD has successfully been cloned and expressed from C. militaris, other important isoforms such as fungal RIPs remain one of the least explored protein families of Cordyceps. Given the clinical success of plant derived RIP based immunotoxins, the development of lectin-RIP conjugates from Cordyceps for targeted cancer therapy represents a particular but underexplored research direction. This review highlighted proteins of cordycipitoid fungi as an underexplored reservoir of bioactive molecules with significant potential for therapeutic development. A more systematic and interdisciplinary research effort will be essential to unlock their value and advance this field.