Protegrin

Protegrins are small peptides containing 16-18 amino acid residues. Protegrins were first discovered in porcine leukocytes and were found to have antimicrobial activity against bacteria, fungi, and some enveloped viruses.[1] The amino acid composition of protegrins contains six positively charged arginine residues and four cysteine residues.[2] Their secondary structure is classified as cysteine-rich β-sheet antimicrobial peptides, AMPs, that display limited sequence similarity to certain defensins and tachyplesins. In solution, the peptides fold to form an anti-parallel β-strand with the structure stabilized by two cysteine bridges formed among the four cysteine residues.[3] Recent studies suggest that protegrins can bind to lipopolysaccharide, a property that may help them to insert into the membranes of gram-negative bacteria and permeabilize them.[4]

Identifiers
SymbolN/A
OPM superfamily203
OPM protein1pg1

Structure

There are five known porcine protegrins, PG-1 to PG-5.[5] Three were identified biochemically and rest of them were deduced from DNA sequences.[6]

Protegrin structures

The protegrins are synthesized from quadiripartite genes as 147 to 149 amino acid precursursors with a cathelin-like propiece.[5][7] Protegrin sequence is similar to certain prodefensins and tachyplesins, antibiotic peptides derived from the horseshoe crab.[1] Protegrin-1 that consists of 18 amino acids, six of which are arginine residues, forms two antiparallel β-sheets with a β-turn. Protegrin-2 is missing two carboxy terminal amino acids. So, Protegrin-2 is shorter than Protegrin-1 and it has one less positive charge. Protegrin-3 substitutes a glycine for an arginine at position 4 and it also has one less positive charge. Protegrin-4 substitutes a phenylalanine for a valine at position 14 and sequences are different in the β-turn. This difference makes protegrin-4 less polar than others and less positively charged. Protegrin-5 substitutes a proline for an arginine with one less positive charge.[5]

Mechanism of action

Protegrin-1 induces membrane disruption by forming a pore/channel that leads to cell death.[8][9] This ability depends on its secondary structure.[10] It forms an oligomeric structure in the membrane that creates a pore. Two ways of the self association of protegrin-1 into a dimeric β-sheet, an antiparallel β-sheet with a turn-next-to-tail association or a parallel β-sheet with a turn-next-to-turn association,[11] were suggested. The activity can be restored by stabilizing the peptide structure with the two disulfide bonds.[12] The interacts with membranes depends on membrane lipid composition[13] and the cationic nature of the protegrin-1 adapts to the amphipathic characteristic which is related to the membrane interaction.[9] The insertion of Protegrin-1 into the lipid layer results in the disordering of lipid packing to the membrane disruption.[13]

Antimicrobial activity

The protegrins are highly microbicidal against Candida albicans,[14] Escherichia coli,[15]Listeria monocytogenes, Neisseria gonorrhoeae,[16] and the virions of the human immunodeficiency virus in vitro under conditions which mimic the tonicity of the extracellular milieu.[1][5][17] The mechanism of this microbicidal activity is believed to involve membrane disruption, similar to many other antibiotic peptides [5][18]

Mimetics as antibiotics

Protegrin-1 (PG-1) peptidomimetics developed by Polyphor AG and the University of Zurich are based on the use of the beta hairpin-stabilizing D-Pro-L-Pro template which promote a beta hairpin loop structure found in PG-I. Fully synthetic cyclic peptide libraries of this peptidomimetic template produced compounds that had an antimicrobial activity like that of PG-1 but with reduced hemolytic activity on human red blood cells.[19] Iterative rounds of synthesis and optimization led to the pseudomonas-specific clinical candidate Murepavadin that successfully completed phase-II clinical tests in hospital patients with life-threatening Pseudomonas lung infections. [20]

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References
  1. Kokryakov VN, Harwig SS, Panyutich EA, Shevchenko AA, Aleshina GM, Shamova OV, Korneva HA, Lehrer RI (July 1993). "Protegrins: leukocyte antimicrobial peptides that combine features of corticostatic defensins and tachyplesins". FEBS Letters. 327 (2): 231–6. doi:10.1016/0014-5793(93)80175-T. PMID 8335113.
  2. Jang H, Ma B, Nussinov R (April 2007). "Conformational study of the protegrin-1 (PG-1) dimer interaction with lipid bilayers and its effect". BMC Structural Biology. 7: 21. doi:10.1186/1472-6807-7-21. PMC 1858697. PMID 17407565.
  3. Kandasamy SK, Larson RG (2007). "Binding modes of protegrin-1, a beta-strand antimicrobial peptide, in lipid bilayers". Molecular Simulation. 9 (10): 799–807. doi:10.1080/08927020701313737.
  4. Yasin B, Harwig SS, Lehrer RI, Wagar EA (March 1996). "Susceptibility of Chlamydia trachomatis to protegrins and defensins". Infection and Immunity. 64 (3): 709–13. doi:10.1128/IAI.64.3.709-713.1996. PMC 173826. PMID 8641770.
  5. Miyasaki KT, Iofel R, Lehrer RI (August 1997). "Sensitivity of periodontal pathogens to the bactericidal activity of synthetic protegrins, antibiotic peptides derived from porcine leukocytes". Journal of Dental Research. 76 (8): 1453–9. doi:10.1177/00220345970760080701. PMID 9240381.
  6. Zhao C, Ganz T, Lehrer RI (July 1995). "The structure of porcine protegrin genes". FEBS Letters. 368 (2): 197–202. doi:10.1016/0014-5793(95)00633-K. PMID 7628604.
  7. Zhao C, Liu L, Lehrer RI (June 1994). "Identification of a new member of the protegrin family by cDNA cloning". FEBS Letters. 346 (2–3): 285–8. doi:10.1016/0014-5793(94)00493-5. PMID 8013647.
  8. Panchal RG, Smart ML, Bowser DN, Williams DA, Petrou S (June 2002). "Pore-forming proteins and their application in biotechnology". Current Pharmaceutical Biotechnology. 3 (2): 99–115. doi:10.2174/1389201023378418. PMID 12022262.
  9. Sokolov Y, Mirzabekov T, Martin DW, Lehrer RI, Kagan BL (August 1999). "Membrane channel formation by antimicrobial protegrins". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1420 (1–2): 23–9. doi:10.1016/S0005-2736(99)00086-3. PMID 10446287.
  10. Drin G, Temsamani J (February 2002). "Translocation of protegrin I through phospholipid membranes: role of peptide folding". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1559 (2): 160–70. doi:10.1016/S0005-2736(01)00447-3. PMID 11853682.
  11. Fahrner RL, Dieckmann T, Harwig SS, Lehrer RI, Eisenberg D, Feigon J (July 1996). "Solution structure of protegrin-1, a broad-spectrum antimicrobial peptide from porcine leukocytes". Chemistry & Biology. 3 (7): 543–50. doi:10.1016/S1074-5521(96)90145-3. PMID 8807886.
  12. Lai JR, Huck BR, Weisblum B, Gellman SH (October 2002). "Design of non-cysteine-containing antimicrobial beta-hairpins: structure-activity relationship studies with linear protegrin-1 analogues" (PDF). Biochemistry. 41 (42): 12835–42. doi:10.1021/bi026127d. PMID 12379126. Archived from the original (PDF) on 2008-12-05. Retrieved 2009-04-27.
  13. Gidalevitz D, Ishitsuka Y, Muresan AS, Konovalov O, Waring AJ, Lehrer RI, Lee KY (May 2003). "Interaction of antimicrobial peptide protegrin with biomembranes". Proceedings of the National Academy of Sciences of the United States of America. 100 (11): 6302–7. doi:10.1073/pnas.0934731100. PMC 164441. PMID 12738879.
  14. Cho Y, Turner JS, Dinh NN, Lehrer RI (June 1998). "Activity of protegrins against yeast-phase Candida albicans". Infection and Immunity. 66 (6): 2486–93. doi:10.1128/IAI.66.6.2486-2493.1998. PMC 108228. PMID 9596706.
  15. Lehrer RI, Barton A, Daher KA, Harwig SS, Ganz T, Selsted ME (August 1989). "Interaction of human defensins with Escherichia coli. Mechanism of bactericidal activity". The Journal of Clinical Investigation. 84 (2): 553–61. doi:10.1172/JCI114198. PMC 548915. PMID 2668334.
  16. Qu XD, Harwig SS, Oren AM, Shafer WM, Lehrer RI (April 1996). "Susceptibility of Neisseria gonorrhoeae to protegrins". Infection and Immunity. 64 (4): 1240–5. doi:10.1128/IAI.64.4.1240-1245.1996. PMC 173910. PMID 8606085. Archived from the original on 2011-07-26. Retrieved 2009-04-27.
  17. Tamamura H, Murakami T, Horiuchi S, Sugihara K, Otaka A, Takada W, Ibuka T, Waki M, Yamamoto N, Fujii N (May 1995). "Synthesis of protegrin-related peptides and their antibacterial and anti-human immunodeficiency virus activity". Chemical & Pharmaceutical Bulletin. 43 (5): 853–8. doi:10.1248/cpb.43.853. PMID 7553971.
  18. Gabay JE (April 1994). "Ubiquitous natural antibiotics". Science. 264 (5157): 373–4. doi:10.1126/science.8153623. PMID 8153623.
  19. Srinivas N, Jetter P, Ueberbacher BJ, Werneburg M, Zerbe K, Steinmann J, Van der Meijden B, Bernardini F, Lederer A, Dias RL, Misson PE, Henze H, Zumbrunn J, Gombert FO, Obrecht D, Hunziker P, Schauer S, Ziegler U, Käch A, Eberl L, Riedel K, DeMarco SJ, Robinson JA (February 2010). "Peptidomimetic antibiotics target outer-membrane biogenesis in Pseudomonas aeruginosa" (PDF). Science. 327 (5968): 1010–3. doi:10.1126/science.1182749. PMID 20167788.
  20. Zerbe K, Moehle K, Robinson JA (June 2017). "Protein Epitope Mimetics: From New Antibiotics to Supramolecular Synthetic Vaccines". Accounts of Chemical Research. 50 (6): 1323–1331. doi:10.1021/acs.accounts.7b00129. PMID 28570824.
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