Protein Engineering, Vol. 15, No. 3, 225-232,
March 2002
© 2002 Oxford University Press
Impact of single-residue mutations on the structure and function of ovispirin/novispirin antimicrobial peptides
1 Department of Microbiology, 2 Department of Medicine, UCLA School of Medicine, Los Angeles, CA 90095 and 3 NMR Facility and 4 Department of Pediatrics, University of Iowa College of Medicine, Iowa City, IA 52242, 5 Department of Chemistry and Center for Biomolecular Structure and Function, Pennsylvania State University, University Park, PA 16802, USA
We studied three model antibacterial peptides that resembled the N-terminal 18 amino acids of SMAP-29, an 
-helical, antimicrobial peptide of sheep. Although the parent compound, ovispirin-1 (KNLRR IIRKI IHIIK KYG), was potently antimicrobial, it was also highly cytotoxic to human epithelial cells and hemolytic for human erythrocytes. Single residue substitutions to ovispirin-1 yielded two substantially less cytotoxic peptides (novispirins), with intact antimicrobial properties. One of these, novispirin G-10, differed from ovispirin-1 only by containing glycine at position 10, instead of isoleucine. The other, novispirin T-7, contained threonine instead of isoleucine at position 7. We determined the three-dimensional solution structures of all three peptides by circular dichroism spectroscopy and two-dimensional nuclear magnetic resonance spectroscopy. Although all retained an amphipathic helical structure in 2,2,2-trifluoroethanol, they manifested subtle fine-structural changes that evidently impacted their activities greatly. These findings show that simple structural modifications can `fine-tune' an antimicrobial peptide to minimize unwanted cytotoxicity while retaining its desired activity.
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