Skip to main content
PMC home page
Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 1997 Nov;41(11):2394–2398. doi: 10.1128/aac.41.11.2394

Novel antimicrobial peptides derived from human immunodeficiency virus type 1 and other lentivirus transmembrane proteins.

S B Tencza 1, J P Douglass 1, D J Creighton Jr 1, R C Montelaro 1, T A Mietzner 1
PMCID: PMC164134  PMID: 9371339

Abstract

We have previously described a conserved set of peptides derived from lentiviral envelope transmembrane proteins that are similar to the natural antimicrobial peptides cecropins and magainins in overall structure but bear no sequence homology to them or other members of their class. We describe here an evaluation of the antimicrobial properties of these virally derived peptides, designated lentivirus lytic peptides (LLPs). The results of this study demonstrate that they are potent and selective antibacterial peptides: the prototype sequence, LLP1, is bactericidal to both gram-positive and gram-negative organisms at micromolar concentrations in 10 mM phosphate buffer. Furthermore, LLP1 kills bacteria quite rapidly, causing a 1,000-fold reduction in viable organisms within 50 s. Peptides corresponding to sequences from three lentivirus envelope proteins were synthesized and characterized. Several of these peptides are selective, killing bacteria at concentrations 50- to 100-fold lower than those required to lyse erythrocytes. Development of antimicrobial agents based on these peptides may lead to improved therapeutics for the management of a variety of infectious diseases.

Full Text

The Full Text of this article is available as a PDF (166.9 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Agerberth B., Lee J. Y., Bergman T., Carlquist M., Boman H. G., Mutt V., Jörnvall H. Amino acid sequence of PR-39. Isolation from pig intestine of a new member of the family of proline-arginine-rich antibacterial peptides. Eur J Biochem. 1991 Dec 18;202(3):849–854. doi: 10.1111/j.1432-1033.1991.tb16442.x. [DOI] [PubMed] [Google Scholar]
  2. Baker M. A., Maloy W. L., Zasloff M., Jacob L. S. Anticancer efficacy of Magainin2 and analogue peptides. Cancer Res. 1993 Jul 1;53(13):3052–3057. [PubMed] [Google Scholar]
  3. Boman H. G. Peptide antibiotics and their role in innate immunity. Annu Rev Immunol. 1995;13:61–92. doi: 10.1146/annurev.iy.13.040195.000425. [DOI] [PubMed] [Google Scholar]
  4. Casteels P., Ampe C., Jacobs F., Vaeck M., Tempst P. Apidaecins: antibacterial peptides from honeybees. EMBO J. 1989 Aug;8(8):2387–2391. doi: 10.1002/j.1460-2075.1989.tb08368.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chernomordik L., Chanturiya A. N., Suss-Toby E., Nora E., Zimmerberg J. An amphipathic peptide from the C-terminal region of the human immunodeficiency virus envelope glycoprotein causes pore formation in membranes. J Virol. 1994 Nov;68(11):7115–7123. doi: 10.1128/jvi.68.11.7115-7123.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chou P. Y., Fasman G. D. Prediction of protein conformation. Biochemistry. 1974 Jan 15;13(2):222–245. doi: 10.1021/bi00699a002. [DOI] [PubMed] [Google Scholar]
  7. Cox J. A., Comte M., Fitton J. E., DeGrado W. F. The interaction of calmodulin with amphiphilic peptides. J Biol Chem. 1985 Feb 25;260(4):2527–2534. [PubMed] [Google Scholar]
  8. Diamond G., Zasloff M., Eck H., Brasseur M., Maloy W. L., Bevins C. L. Tracheal antimicrobial peptide, a cysteine-rich peptide from mammalian tracheal mucosa: peptide isolation and cloning of a cDNA. Proc Natl Acad Sci U S A. 1991 May 1;88(9):3952–3956. doi: 10.1073/pnas.88.9.3952. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Eisenberg D., Schwarz E., Komaromy M., Wall R. Analysis of membrane and surface protein sequences with the hydrophobic moment plot. J Mol Biol. 1984 Oct 15;179(1):125–142. doi: 10.1016/0022-2836(84)90309-7. [DOI] [PubMed] [Google Scholar]
  10. Eisenberg D., Wesson M. The most highly amphiphilic alpha-helices include two amino acid segments in human immunodeficiency virus glycoprotein 41. Biopolymers. 1990 Jan;29(1):171–177. doi: 10.1002/bip.360290122. [DOI] [PubMed] [Google Scholar]
  11. Fontenot J. D., Ball J. M., Miller M. A., David C. M., Montelaro R. C. A survey of potential problems and quality control in peptide synthesis by the fluorenylmethoxycarbonyl procedure. Pept Res. 1991 Jan-Feb;4(1):19–25. [PubMed] [Google Scholar]
  12. Fujii G., Horvath S., Woodward S., Eiserling F., Eisenberg D. A molecular model for membrane fusion based on solution studies of an amphiphilic peptide from HIV gp41. Protein Sci. 1992 Nov;1(11):1454–1464. doi: 10.1002/pro.5560011107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Gawrisch K., Han K. H., Yang J. S., Bergelson L. D., Ferretti J. A. Interaction of peptide fragment 828-848 of the envelope glycoprotein of human immunodeficiency virus type I with lipid bilayers. Biochemistry. 1993 Mar 30;32(12):3112–3118. doi: 10.1021/bi00063a024. [DOI] [PubMed] [Google Scholar]
  14. Habermann E. Bee and wasp venoms. Science. 1972 Jul 28;177(4046):314–322. doi: 10.1126/science.177.4046.314. [DOI] [PubMed] [Google Scholar]
  15. Hancock R. E. Peptide antibiotics. Lancet. 1997 Feb 8;349(9049):418–422. doi: 10.1016/S0140-6736(97)80051-7. [DOI] [PubMed] [Google Scholar]
  16. Hill C. P., Yee J., Selsted M. E., Eisenberg D. Crystal structure of defensin HNP-3, an amphiphilic dimer: mechanisms of membrane permeabilization. Science. 1991 Mar 22;251(5000):1481–1485. doi: 10.1126/science.2006422. [DOI] [PubMed] [Google Scholar]
  17. Kaiser E. T., Kézdy F. J. Peptides with affinity for membranes. Annu Rev Biophys Biophys Chem. 1987;16:561–581. doi: 10.1146/annurev.bb.16.060187.003021. [DOI] [PubMed] [Google Scholar]
  18. Kelley K. J. Using host defenses to fight infectious diseases. Nat Biotechnol. 1996 May;14(5):587–590. doi: 10.1038/nbt0596-587. [DOI] [PubMed] [Google Scholar]
  19. Lee J. Y., Boman A., Sun C. X., Andersson M., Jörnvall H., Mutt V., Boman H. G. Antibacterial peptides from pig intestine: isolation of a mammalian cecropin. Proc Natl Acad Sci U S A. 1989 Dec;86(23):9159–9162. doi: 10.1073/pnas.86.23.9159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Lehrer R. I., Selsted M. E., Szklarek D., Fleischmann J. Antibacterial activity of microbicidal cationic proteins 1 and 2, natural peptide antibiotics of rabbit lung macrophages. Infect Immun. 1983 Oct;42(1):10–14. doi: 10.1128/iai.42.1.10-14.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Miller M. A., Cloyd M. W., Liebmann J., Rinaldo C. R., Jr, Islam K. R., Wang S. Z., Mietzner T. A., Montelaro R. C. Alterations in cell membrane permeability by the lentivirus lytic peptide (LLP-1) of HIV-1 transmembrane protein. Virology. 1993 Sep;196(1):89–100. doi: 10.1006/viro.1993.1457. [DOI] [PubMed] [Google Scholar]
  22. Miller M. A., Garry R. F., Jaynes J. M., Montelaro R. C. A structural correlation between lentivirus transmembrane proteins and natural cytolytic peptides. AIDS Res Hum Retroviruses. 1991 Jun;7(6):511–519. doi: 10.1089/aid.1991.7.511. [DOI] [PubMed] [Google Scholar]
  23. Miller M. A., Mietzner T. A., Cloyd M. W., Robey W. G., Montelaro R. C. Identification of a calmodulin-binding and inhibitory peptide domain in the HIV-1 transmembrane glycoprotein. AIDS Res Hum Retroviruses. 1993 Nov;9(11):1057–1066. doi: 10.1089/aid.1993.9.1057. [DOI] [PubMed] [Google Scholar]
  24. Moore A. J., Devine D. A., Bibby M. C. Preliminary experimental anticancer activity of cecropins. Pept Res. 1994 Sep-Oct;7(5):265–269. [PubMed] [Google Scholar]
  25. Nicolas P., Mor A. Peptides as weapons against microorganisms in the chemical defense system of vertebrates. Annu Rev Microbiol. 1995;49:277–304. doi: 10.1146/annurev.mi.49.100195.001425. [DOI] [PubMed] [Google Scholar]
  26. Pearson R. D., Steigbigel R. T., Davis H. T., Chapman S. W. Method of reliable determination of minimal lethal antibiotic concentrations. Antimicrob Agents Chemother. 1980 Nov;18(5):699–708. doi: 10.1128/aac.18.5.699. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Rushlow K., Olsen K., Stiegler G., Payne S. L., Montelaro R. C., Issel C. J. Lentivirus genomic organization: the complete nucleotide sequence of the env gene region of equine infectious anemia virus. Virology. 1986 Dec;155(2):309–321. doi: 10.1016/0042-6822(86)90195-9. [DOI] [PubMed] [Google Scholar]
  28. Sarin V. K., Kent S. B., Tam J. P., Merrifield R. B. Quantitative monitoring of solid-phase peptide synthesis by the ninhydrin reaction. Anal Biochem. 1981 Oct;117(1):147–157. doi: 10.1016/0003-2697(81)90704-1. [DOI] [PubMed] [Google Scholar]
  29. Schonwetter B. S., Stolzenberg E. D., Zasloff M. A. Epithelial antibiotics induced at sites of inflammation. Science. 1995 Mar 17;267(5204):1645–1648. doi: 10.1126/science.7886453. [DOI] [PubMed] [Google Scholar]
  30. Selsted M. E., Brown D. M., DeLange R. J., Lehrer R. I. Primary structures of MCP-1 and MCP-2, natural peptide antibiotics of rabbit lung macrophages. J Biol Chem. 1983 Dec 10;258(23):14485–14489. [PubMed] [Google Scholar]
  31. Srinivas S. K., Srinivas R. V., Anantharamaiah G. M., Segrest J. P., Compans R. W. Membrane interactions of synthetic peptides corresponding to amphipathic helical segments of the human immunodeficiency virus type-1 envelope glycoprotein. J Biol Chem. 1992 Apr 5;267(10):7121–7127. [PubMed] [Google Scholar]
  32. Steiner H., Hultmark D., Engström A., Bennich H., Boman H. G. Sequence and specificity of two antibacterial proteins involved in insect immunity. Nature. 1981 Jul 16;292(5820):246–248. doi: 10.1038/292246a0. [DOI] [PubMed] [Google Scholar]
  33. Tencza S. B., Mietzner T. A., Montelaro R. C. Calmodulin-binding function of LLP segments from the HIV type 1 transmembrane protein is conserved among natural sequence variants. AIDS Res Hum Retroviruses. 1997 Feb 10;13(3):263–269. doi: 10.1089/aid.1997.13.263. [DOI] [PubMed] [Google Scholar]
  34. Tencza S. B., Miller M. A., Islam K., Mietzner T. A., Montelaro R. C. Effect of amino acid substitutions on calmodulin binding and cytolytic properties of the LLP-1 peptide segment of human immunodeficiency virus type 1 transmembrane protein. J Virol. 1995 Aug;69(8):5199–5202. doi: 10.1128/jvi.69.8.5199-5202.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Yuan T., Mietzner T. A., Montelaro R. C., Vogel H. J. Characterization of the calmodulin binding domain of SIV transmembrane glycoprotein by NMR and CD spectroscopy. Biochemistry. 1995 Aug 22;34(33):10690–10696. doi: 10.1021/bi00033a045. [DOI] [PubMed] [Google Scholar]
  36. Zasloff M. Magainins, a class of antimicrobial peptides from Xenopus skin: isolation, characterization of two active forms, and partial cDNA sequence of a precursor. Proc Natl Acad Sci U S A. 1987 Aug;84(15):5449–5453. doi: 10.1073/pnas.84.15.5449. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. van Hofsten P., Faye I., Kockum K., Lee J. Y., Xanthopoulos K. G., Boman I. A., Boman H. G., Engström A., Andreu D., Merrifield R. B. Molecular cloning, cDNA sequencing, and chemical synthesis of cecropin B from Hyalophora cecropia. Proc Natl Acad Sci U S A. 1985 Apr;82(8):2240–2243. doi: 10.1073/pnas.82.8.2240. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Antimicrobial Agents and Chemotherapy are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES