Tachyplesin: Difference between revisions

<StructureSection load='1MA2' size='340' side='right' caption='[[1ma2]]' scene='67/671725/First_scene/2'>

Tachyplesin I (TP-I) is an [http://en.wikipedia.org/wiki/Antimicrobial_peptides antimicrobial polypeptide] originally detected in the leukocytes of Japanese [http://en.wikipedia.org/wiki/Horseshoe_crab Horse Shoe Crab]. It has been reported to inhibit the growth  of [http://en.wikipedia.org/wiki/Bacteria bacteria], [http://en.wikipedia.org/wiki/Fungus fungui] and [http://en.wikipedia.org/wiki/Virus viruses].

Among all the existing interactions, the cysteine bridges being considered as the principal contributors of the hairpin loop structure. To test this three linear derivatives of TP-I (<scene name='67/671725/1ma4/3'>TPY4</scene>, TPF4 and TPA4) were created, in which the bridging cysteine residues are systematically replaced with tyrosine, phenylalanine, and alanine, respectively<ref name=Laederach>PMID:12369825</ref><ref name=Kushibiki>PMID:24389234</ref>. The linear derivatives of TP-I are mentioned below:

[[Image:Seq TPI.jpg|750px]]

Of this 3 linear derivatives of TP-I, NMR structural investigations had shown that TPA4 was unstructured in solution. Also, TPA4 was inactive in terms of antimicrobial activity. In contrast, TPY4 and TPF4 adapt hairpin loop structure and also retain their antimicrobial properties, typical to TP-I. Therefore, the hairpin properties of the peptide seems to be important for recognition of LPS and its biological activities.

Besides replacement of cysteines, deletions was also performed in TP-I which yielded the surprising result of a hairpin loop that was seen, by NMR structure in LPS, in the <scene name='67/671725/Cdt/1'>Cysteine Deleted Tachyplesin</scene> (CDT). Thus, CTD  with sequence NH₂-Lys-Trp-Phe-Arg-Val-Tyr-Arg-Gly-Ile-Tyr-Arg-Arg-Arg-CONH₂ did not have disulphide linkage, but was found to have broad spectrum of bactericidal activity. Specifically, CDT has been demonstrated to markedly inhibit the growth of [http://en.wikipedia.org/wiki/Escherichia_coli <i>Escherichia coli</i>] and [http://en.wikipedia.org/wiki/Listeria_monocytogenes <i>Listeria monocytogenes</i>] akin to TP-I, even with lower minimum inhibitory concentration (MIC) values.

The β-hairpin structure displays an extended <font color='darkblue'>positively charged</font> surface patch of <scene name='67/671725/Cdtr4r7r12r13/3'>residues Arg 4, 7, 12 and 13</scene>. These positively charged basic residues interacts with the anionic phosphate groups of LPS, that leads to a plausible disruption or fluidization of LPS structures. This facilitates traversal of the peptide through the LPS-outer membrane<ref name=Saravanan>PMID:22464970</ref>.

Evidences suggest that TP-I has ability to permeabilize the cell membranes of pathogens.<ref name=Laederach>PMID:12369825</ref>. Also, LPS and DNA being the potential biological targets of the peptide, its antimicrobial activity might be exploited. Eyeing the potential of TP-I, it has been insetred successfully in genome of ''Ornithogalum dubium'' and ''Ornithogalum thyrsoides''. These ornamentals plants were originally sensitive to soft rot erwinias (SREs) and insertion of TP-I in the plants has successfully protected them without affecting their normal physiology <ref name=Lipsky>PMID:25438795</ref>.

It was found that the synthetic Tachyplesin conjugated to the integrin homing domain (RGD-Tachyplesin) can inhibit the [http://en.wikipedia.org/wiki/Cell_growth proliferation] of TSU tumor cells [http://en.wikipedia.org/wiki/Prostate_cancer prostate cancer]  and B16 [http://en.wikipedia.org/wiki/Melanoma melanoma] cells as well as [http://en.wikipedia.org/wiki/Endothelium endothelial cells] in a dose-dependent manner <i>in vitro</i> and reduce tumor growth <i>in vivo</i> by inducing [http://en.wikipedia.org/wiki/Apoptosis apoptosis].<ref name=Chen>PMID:11289111‏</ref>. Besides this RGD-Tachyplesin can activate caspases and induce Fas ligand, which are the markers for programmed cell death (PCD). Collectively, suppression of tumor associated cell and induction of programmed cell death will eventually act as therapy for cancer and tumor cells.

*[[Tachyplesin I 3D structures]]