Planta Med 2015; 81 - PT20
DOI: 10.1055/s-0035-1556398

Novel 22-mer peptaibols isolated from Tolypocladium sp. with potent antitumor activities

L Du 1, 2, AL Risinger 4, 5, CA Mitchell 1, 2, BW Stamps 3, N Pan 2, JB King 1, 2, Z Yang 2, BS Stevenson 3, RH Cichewicz 1, 2
  • 1Natural Products Discovery Group, Institute for Natural Products Applications and Research Technologies, University of Oklahoma
  • 2Department of Chemistry and Biochemistry, University of Oklahoma
  • 3Department of Microbiology and Plant Biology, University of Oklahoma, Norman, OK 73019
  • 4Department of Pharmacology, University of Texas Health Science Center
  • 5Cancer Therapy & Research Center, University of Texas Health Science Center, San Antonio, TX 78229

Genome mining of a Tolypocladium sp. isolate led to the purification and identification of gichigamin A (1), the first 22-mer and longest peptaibol from a natural source. The β-alanine rich sequence of 1 results in the assembly of an unprecedented 310-like helical structure, which was revealed by single-crystal X-ray diffraction analysis. The unique structural character of 1 was determined to be essential for its unexpected high penetrability through cell membranes. As a result, gichigamin A (1) exhibited potent in vitro cytotoxicity by direct disruption of mitochondrial function and the capability to inhibit MIA PaCa-2 xenograft tumor growth in nude mice.