Bactericidal and tumoricidal activities of synthetic peptides derived from granulysin.
Granulysin, a 9-kDa protein localized to human CTL and NK cell granules, is cytolytic against tumor cells and microbes. Molecular modeling predicts that granulysin is composed of five alpha-helices separated by short loop regions. In this report, synthetic peptides corresponding to the linear granulysin sequence were characterized for lytic activity. Peptides corresponding to the central region of granulysin lyse bacteria, human cells, and synthetic liposomes, while peptides corresponding to the amino or carboxyl regions are not lytic. Peptides corresponding to either helix 2 or helix 3 lyse bacteria, while lysis of human cells and liposomes is dependent on the helix 3 sequence. Peptides in which positively charged arginine residues are substituted with neutral glutamine exhibit reduced lysis of all three targets. While reduction of recombinant 9-kDa granulysin increases lysis of Jurkat cells, reduction of cysteine-containing granulysin peptides decreases lysis of Jurkat cells. In contrast, lysis of bacteria by recombinant granulysin or by cysteine-containing granulysin peptides is unaffected by reducing conditions. Jurkat cells transfected with either CrmA or Bcl-2 are protected from lysis by recombinant granulysin or the peptides. Differential activity of granulysin peptides against tumor cells and bacteria may be exploited to develop specific antibiotics without toxicity for mammalian cells.
Wang
Z
Z
Departments of Cardiothoracic Surgery and Pediatrics, Stanford University, Stanford, CA 94305, USA.
Choice
E
E
Kaspar
A
A
Hanson
D
D
Okada
S
S
Lyu
S C
SC
Krensky
A M
AM
Clayberger
C
C
D000276:Adjuvants, Immunologic / Q000138:chemical synthesis / Q000378:metabolism / Q000633:toxicity; D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000633:toxicity*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D001433:Bacteriolysis / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D006358:Hot Temperature; D006801:Humans; D019169:Jurkat Cells / Q000187:drug effects; D007694:Killer Cells, Natural / Q000276:immunology; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000378:metabolism / Q000633:toxicity*; D017433:Protein Structure, Secondary; D012486:Salmonella typhimurium / Q000187:drug effects*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D000276:Adjuvants, Immunologic; D000900:Anti-Bacterial Agents; D000945:Antigens, Differentiation, T-Lymphocyte; D000970:Antineoplastic Agents; C075005:GNLY protein, human; D010446:Peptide Fragments