Abstract
Host defense peptides (HDPs) comprise a heterogeneous group of evolutionarily conserved and biologically active small molecules that are produced by different organisms. HDPs are widely researched because they often have multiple biological activities, for example antimicrobial, immunomodulatory and anticancer activity. In this context, in this review we focus on cryptic HDPs, molecules derived specifically from proteolytic processing of endogenous precursor proteins. Here, we explore the biological activity of such molecules and we further discuss the development of optimized sequences based on these natural cryptic HDPs. In addition, we present clinical-phase studies of cryptic HDPs (natural or optimized), and point out the possible applicability of these molecules in medicinal chemistry.
Keywords: Cryptic peptides, Bioactive peptides, HDPs, Precursor protein, Optimized HDPs, Cryptic HDPs.
Graphical Abstract
[http://dx.doi.org/10.4103/jomfp.JOMFP_113_16] [PMID: 30158778]
[http://dx.doi.org/10.1007/s00018-007-6475-6] [PMID: 17310278]
[http://dx.doi.org/10.2174/1568026617666170105144830] [PMID: 28056743]
[http://dx.doi.org/10.1128/AAC.49.5.1727-1732.2005] [PMID: 15855488]
[http://dx.doi.org/10.2174/1568026615666150703121819] [PMID: 26139111]
[http://dx.doi.org/10.3390/ph7050545] [PMID: 24828484]
[http://dx.doi.org/10.1093/emboj/19.7.1525] [PMID: 10747021]
[http://dx.doi.org/10.1177/1753425915610643] [PMID: 26511058]
[http://dx.doi.org/10.3389/fmicb.2019.01257] [PMID: 31231341]
[http://dx.doi.org/10.1038/nbt1267] [PMID: 17160061]
[http://dx.doi.org/10.1093/nar/gkv1278] [PMID: 26602694]
[http://dx.doi.org/10.1186/s12934-015-0302-9] [PMID: 26338197]
[http://dx.doi.org/10.2174/1381612824666180327165012] [PMID: 29589536]
[http://dx.doi.org/10.1016/j.peptides.2007.10.005] [PMID: 18023928]
[http://dx.doi.org/10.1073/pnas.74.7.3014] [PMID: 197529]
[http://dx.doi.org/10.1016/0968-0004(81)90068-2]
[http://dx.doi.org/10.1038/278423a0] [PMID: 221818]
[http://dx.doi.org/10.1073/pnas.74.12.5300] [PMID: 202948]
[http://dx.doi.org/10.1208/s12248-011-9252-2] [PMID: 21327597]
[http://dx.doi.org/10.1016/j.drudis.2006.02.003] [PMID: 16580972]
[PMID: 16676270]
[http://dx.doi.org/10.1016/j.biotechadv.2011.01.001] [PMID: 21238564]
[http://dx.doi.org/10.1038/nrd3591] [PMID: 22173434]
[http://dx.doi.org/10.1002/(SICI)1097-0282(1997)43:2<171:AID-BIP10>3.0.CO;2-O] [PMID: 9216253]
[http://dx.doi.org/10.2174/0929866522666160512151313] [PMID: 27173646]
[http://dx.doi.org/10.1002/bip.20687] [PMID: 17245751]
[http://dx.doi.org/10.1371/journal.ppat.1000857] [PMID: 20421939]
[http://dx.doi.org/10.1016/j.matbio.2016.09.003] [PMID: 27613501]
[http://dx.doi.org/10.1074/jbc.M409841200] [PMID: 15591058]
[http://dx.doi.org/10.1074/jbc.M210445200] [PMID: 12435733]
[http://dx.doi.org/10.1074/jbc.M114.556530] [PMID: 24737315]
[http://dx.doi.org/10.1074/jbc.M001956200] [PMID: 10766752]
[http://dx.doi.org/10.2337/diabetes.53.7.1831] [PMID: 15220208]
[http://dx.doi.org/10.1016/j.bbrc.2003.11.003] [PMID: 14680836]
[http://dx.doi.org/10.1074/jbc.275.2.1209] [PMID: 10625665]
[http://dx.doi.org/10.1016/S0306-4522(98)00338-8] [PMID: 10199602]
[http://dx.doi.org/10.1016/S0006-8993(01)03148-1] [PMID: 11730700]
[http://dx.doi.org/10.1080/08998280.2006.11928171] [PMID: 17252042]
[http://dx.doi.org/10.1016/S1570-0232(03)00245-9] [PMID: 12798194]
[http://dx.doi.org/10.1093/humrep/den318] [PMID: 18786935]
[http://dx.doi.org/10.1208/s12248-010-9217-x] [PMID: 20811967]
[http://dx.doi.org/10.1074/jbc.M110.127019] [PMID: 20592020]
[http://dx.doi.org/10.1021/bm400150c] [PMID: 23537377]
[http://dx.doi.org/10.1128/AAC.01515-10] [PMID: 21402837]
[http://dx.doi.org/10.1021/acs.bioconjchem.6b00013] [PMID: 26938833]
[http://dx.doi.org/10.1371/journal.pone.0051313] [PMID: 23272096]
[http://dx.doi.org/10.1038/s41598-017-11464-x] [PMID: 28894159]
[http://dx.doi.org/10.1152/ajpgi.00237.2014] [PMID: 25214403]
[http://dx.doi.org/10.1016/j.csbj.2017.05.003] [PMID: 28660014]
[http://dx.doi.org/10.1016/S0196-9781(00)00165-0] [PMID: 10793212]
[PMID: 15796184]
[http://dx.doi.org/10.1006/exnr.2001.7541] [PMID: 11161595]
[http://dx.doi.org/10.1371/journal.pone.0008191] [PMID: 19997607]
[http://dx.doi.org/10.1111/febs.13725] [PMID: 27028511]
[http://dx.doi.org/10.1002/psc.3095] [PMID: 29900637]
[http://dx.doi.org/10.1021/acssynbio.8b00084] [PMID: 30124040]
[http://dx.doi.org/10.1016/j.bbagen.2017.04.009] [PMID: 28454736]
[http://dx.doi.org/10.1021/jf2020396] [PMID: 21851100]
[http://dx.doi.org/10.1016/j.ejps.2017.07.005] [PMID: 28711715]
[http://dx.doi.org/10.1159/000327016] [PMID: 21576923]
[http://dx.doi.org/10.1128/IAI.67.3.1353-1358.1999] [PMID: 10024582]
[http://dx.doi.org/10.1074/jbc.M500266200] [PMID: 15687491]
[http://dx.doi.org/10.1093/jac/dkg219] [PMID: 12697647]
[http://dx.doi.org/10.1016/j.femsim.2004.02.006] [PMID: 15145458]
[http://dx.doi.org/10.1128/IAI.69.3.1469-1476.2001] [PMID: 11179314]
[http://dx.doi.org/10.1128/AAC.48.12.4919-4921.2004] [PMID: 15561882]
[http://dx.doi.org/10.1086/522427] [PMID: 17922408]
[http://dx.doi.org/10.1128/AAC.00652-09] [PMID: 19933796]
[http://dx.doi.org/10.1007/s10534-010-9322-4] [PMID: 20238236]
[http://dx.doi.org/10.1371/journal.pone.0052772] [PMID: 23300768]
[http://dx.doi.org/10.1186/s12866-016-0750-3] [PMID: 27349742]
[http://dx.doi.org/10.1016/0167-4838(92)90346-F] [PMID: 1599934]
[http://dx.doi.org/10.1007/s00018-005-5373-z] [PMID: 16261252]
[http://dx.doi.org/10.1016/S0168-1702(99)00121-5] [PMID: 10653917]
[http://dx.doi.org/10.1007/s00018-005-5228-7] [PMID: 16261265]
[http://dx.doi.org/10.1016/j.peptides.2005.02.011] [PMID: 16112390]
[PMID: 16936803]
[http://dx.doi.org/10.1292/jvms.63.187] [PMID: 11258458]
[http://dx.doi.org/10.1007/s10534-011-9465-y] [PMID: 21607695]
[http://dx.doi.org/10.1016/S0014-5793(01)02233-5] [PMID: 11248238]
[http://dx.doi.org/10.1371/journal.pone.0028197] [PMID: 22164243]
[http://dx.doi.org/10.1271/bbb.60.521] [PMID: 8901116]
[http://dx.doi.org/10.1006/cimm.1997.1246] [PMID: 9682001]
[http://dx.doi.org/10.1002/jcp.24151] [PMID: 22740381]
[http://dx.doi.org/10.3390/molecules21060752] [PMID: 27294909]
[http://dx.doi.org/10.1155/2013/390230] [PMID: 23554820]
[http://dx.doi.org/10.1515/BC.2005.017] [PMID: 15843157]
[http://dx.doi.org/10.1016/j.peptides.2005.03.056] [PMID: 15946771]
[http://dx.doi.org/10.1007/s10534-010-9295-3] [PMID: 20140481]
[http://dx.doi.org/10.1007/s12010-016-2059-y] [PMID: 27022750]
[http://dx.doi.org/10.1007/s10534-010-9306-4] [PMID: 20195887]
[http://dx.doi.org/10.1016/j.foodchem.2007.08.036]
[http://dx.doi.org/10.1016/j.peptides.2014.07.005] [PMID: 25020248]
[http://dx.doi.org/10.1111/j.1750-3841.2007.00571.x] [PMID: 18034756]
[http://dx.doi.org/10.1021/jf071408j] [PMID: 18163567]
[http://dx.doi.org/10.1074/jbc.M803913200] [PMID: 18768476]
[http://dx.doi.org/10.1016/j.foodres.2004.07.005]
[http://dx.doi.org/10.1016/j.peptides.2011.05.020] [PMID: 21640151]
[http://dx.doi.org/10.1016/j.jff.2015.11.020]
[http://dx.doi.org/10.1016/j.bbrc.2015.04.091] [PMID: 25934151]
[http://dx.doi.org/10.1016/j.bbrc.2008.10.102] [PMID: 18976634]
[http://dx.doi.org/10.1006/bbrc.1996.0071] [PMID: 8573171]
[http://dx.doi.org/10.1016/j.peptides.2012.09.022] [PMID: 23022591]
[http://dx.doi.org/10.1006/bbrc.1998.8159] [PMID: 9514864]
[http://dx.doi.org/10.1016/j.bbamem.2011.12.023] [PMID: 22230351]
[http://dx.doi.org/10.1002/prot.22074] [PMID: 18452210]
[http://dx.doi.org/10.1016/j.peptides.2012.01.015] [PMID: 22306477]
[http://dx.doi.org/10.1021/bi0004549] [PMID: 10913273]
[http://dx.doi.org/10.1073/pnas.150518097] [PMID: 10890923]
[http://dx.doi.org/10.3892/etm.2013.1231] [PMID: 24137305]
[http://dx.doi.org/10.3136/nskkk.55.602]
[http://dx.doi.org/10.1021/jf072669w] [PMID: 18808143]
[http://dx.doi.org/10.1021/jf100388w] [PMID: 20459131]
[http://dx.doi.org/10.1016/j.fshw.2018.02.002]
[http://dx.doi.org/10.1002/food.200390081] [PMID: 14609094]
[http://dx.doi.org/10.1016/j.foodchem.2005.06.050]
[http://dx.doi.org/10.1111/j.1365-2621.2006.tb15612.x]
[http://dx.doi.org/10.1002/biof.5520120122] [PMID: 11216476]
[http://dx.doi.org/10.1002/biof.5520120124] [PMID: 11216478]
[http://dx.doi.org/10.1016/j.febslet.2015.08.018] [PMID: 26297825]
[http://dx.doi.org/10.1186/s40104-017-0153-9] [PMID: 28286649]
[http://dx.doi.org/10.2174/1381612033454838] [PMID: 12769740]
[http://dx.doi.org/10.1139/o06-042] [PMID: 16936807]
[http://dx.doi.org/10.3390/cancers3033279] [PMID: 24212956]
[http://dx.doi.org/10.4317/medoral.19087] [PMID: 23986016]
[http://dx.doi.org/10.7759/cureus.1403] [PMID: 28852600]
[http://dx.doi.org/10.3389/fcimb.2016.00194] [PMID: 28083516]
[http://dx.doi.org/10.1016/j.cbpa.2011.02.015] [PMID: 21419690]
[http://dx.doi.org/10.1161/01.ATV.0000067935.02679.B0] [PMID: 12649091]
[PMID: 25013401]
[http://dx.doi.org/10.1161/01.STR.0000226901.34927.10] [PMID: 16741184]
[http://dx.doi.org/10.1161/01.ATV.0000067937.93716.DB] [PMID: 12649092]
[http://dx.doi.org/10.1111/j.1365-2796.2008.01995.x] [PMID: 18783480]
[http://dx.doi.org/10.1007/s12026-013-8383-1] [PMID: 23345063]
[http://dx.doi.org/10.1161/ATVBAHA.109.202671] [PMID: 20167655]
[http://dx.doi.org/10.1371/journal.pone.0146552] [PMID: 26808536]
[http://dx.doi.org/10.1080/00365540110026692] [PMID: 11515760]
[http://dx.doi.org/10.1111/j.1399-3011.2001.00821.x] [PMID: 11298926]
[http://dx.doi.org/10.1007/s12017-015-8341-2] [PMID: 25613838]
[http://dx.doi.org/10.1080/21678707.2016.1229181] [PMID: 28163986]
[http://dx.doi.org/10.1212/WNL.0000000000007316] [PMID: 30918097]
[http://dx.doi.org/10.1007/s40487-017-0055-1]