Cell-Penetrating Peptides
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Dr. Yosuke Demizu received his Ph.D. in pharmaceutical sciences from Kyushu University in 2006. He joined the faculty of Tokushima Bunri University (2004-2005) and then at Nagasaki University (2006-2008). He moved to the National Institute of Health Sciences (NIHS) as a researcher, and was promoted to head the division of organic chemistry in 2017. He has authored over 150 scientific publications and has received several awards, including the Incentive Award in Synthetic Organic Chemistry, Japan (2006, 2010) and the Award for Young Investigators from the Japanese Peptide Society (2014).
Inhalt
PART 1: DESGIN OF CPPS
Classification of cell-penetrating peptides
Arginine-rich cell-penetrating peptides: recent advances of design and applications for intracellular delivery
Cationic cell-penetrating peptides
Amphipathic cell-penetrating peptides
Hydrophobic cell-penetrating peptides
Foldamers
PART 2: MECHANISM OF CPPS
Peptide Structure: Electrophysiological analysis, nuclear magnetic resonance analysis, and molecular dynamics simulation of direct penetration of cell-penetrating peptides through bilayer lipid membranes
Cellular uptake mechanisms of arginine-rich cell-penetrating peptides
Endosomal escape
Pharmacokinetics of therapeutic and diagnostic agents conjugated with cell-penetrating peptides
PART 3: DELIVERY TOOLS
Drug delivery
Peptide & protein delivery
Cell-penetrating peptides for nucleic acid delivery
PPMOs: a case study for cell-penetrating peptide application
Cell penetrating peptide-conjugated polymer micelles for pDNA/siRNA delivery
Lipid-based nanoparticles using cell-penetrating peptides
PART 4: APPLICATIONS
Cell-penetrating peptides as tools to facilitate oral delivery of biopharmaceuticals
Intranasal delivery
Clinical trials
Applications in plants
1
Introduction
Makoto Oba1 and Yosuke Demizu2
1 Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan
2 National Institute of Health Sciences, Division of Organic Chemistry, Kanagawa, Japan
Cell-penetrating peptides (CPPs) are short peptides (in general composed of 5-30 amino acids) that can be efficiently internalized into cells and have great potential for the delivery of membrane-impermeable bioactive molecules into cells. The CPP is sometimes called a protein transduction domain (PTD) or Trojan peptide. In 1988, such a peptide was first discovered in human immunodeficiency virus type 1 (HIV-1) protein transactivator of transcription (Tat). Since then, numerous sequences of CPPs have been discovered in natural peptides/proteins such as Tat peptide and CPPs have also been artificially designed. Furthermore, the cell-penetrating mechanisms of CPPs in vitro and in vivo have been investigated, and CPPs have been used as delivery tools for drugs, peptides, proteins, nucleic acids, and nanoparticles. Several CPPs are currently under investigation in clinical trials. More than 500 research papers per year have been published since 2012 with a keyword of "CPP" or "PTD," and numbers have reached slightly less than 1000 for the last few years. From these numbers, we can understand the usefulness and significance of CPPs.
This book describes the design, mechanism, delivery tools, and applications of CPPs. There are several books and journals' special issues on CPPs. However, none has previously categorized such topics. On the topic of design, the classification of CPPs is first described based on their characteristics, and then, typical types of CPPs (cationic, amphipathic, and hydrophobic peptides) and Arg-rich peptides and foldamers are introduced. The topic of mechanism deals with important factors of CPPs, such as peptide secondary structure, cellular uptake, endosomal escape, and pharmacokinetics in vivo. The topic of delivery tools is categorized based on cargos, drugs, peptides and proteins, nucleic acids, and morpholino oligomers. Furthermore, CPPs assisting in the efficient delivery of nano-sized drug delivery systems, polymeric micelles, and lipid-based nanoparticles are introduced as delivery tools. The final topic of applications covers oral delivery and intranasal delivery using CPPs, CPPs in clinical trials, and applications in plants. Table 1.1 lists the representative CPPs introduced in this book. We hope that this book will be useful for readers studying and treating CPPs now and in the future.
Table 1.1 Lists of CPPs introduced in this book.
CPP Sequence Ref. [C12-R4] Cyclic(CXRRRR)X: (R,S)-2-amino tetradecanoic acid [1] [R6W3] Cyclic(CRRWWRRWRR) [1] A2-17 LRKLRKRLLRLWKLRKR [2] A2-17KR LRRLRRRLLRLWRLRRR [2] AA3H MASIWVGHRG [3] Ac5cNH2 peptide (RRX)3
X: Ac5cNH2, 1,3-diaminocyclopentanecarboxylic acid [4] Ac5cGu peptide (RRX)3
X: Ac5cGu, 1-amino-3-guanidinocyclopentanecarboxylic acid [4] Ac6cNH2 peptide (RRX)3
X: Ac6cNH2, 1,4-diaminocyclohexanecarboxylic acid [5] Amphipathic ß-peptide [(S,S)-ACHC-ß3hArg-ß3hArg]3
ACHC: trans-2-aminocyclohexanecarboxylic acid
ß3hArg: ß3-homoarginine [6] ApiC2Gu peptide (RRX)3
X: ApiC2Gu, 4-aminopiperidine-4-carboxylic acid derivative [7] aR7W2 RRRWRRWRR [8] ARF (1-22) MVRRFLVTLRIRRACGPPRVRV [9] ARF (19-31) RVRVFVVHIPRLT [9] ß-Heptaarginine (ß3hArg)7
ß3hArg: ß3-homoarginine [10] ß-Heptalysine (ß3hLys)7
ß3hLys: ß3-homolysine [10] ß-Tat ß3hArg-(ß3hLys)2-(ß3hArg)2-ß3hGln-(ß3hArg)3 [11] Bac15-24 RRIRPRPPRLPRPRPRPLPFPRPG [12] Bip2 VPTLK [13] Block3 LLULLULLUGGGRRRRRRRRR
U: Aib, 2-aminoisobutyric acid [14] BP100 KKLFKKKKILKYL [15] bPrPp (1-30) MVKSKIGSWILVLFVAMWSDVGLCKKRPKP [16] Butyl-TH AGYLLGHBINLHBHBLAHBLUHBHBIL
U: Aib, 2-aminoisobutyric acid; HB: 3-butylhistidine [17] C105Y CSIPPEVKFNKPFVYLI [18] CADY GLWRALWRLLRSLWRLLWRA-cysteamide [19] CH2R4H2C CHHRRRRHHC [20] cLK Cyclic Ac-CKKLLKLLKKLLKLGGLKKLLKLLKKLLKLLK
Crosslink between the side chains of C and K [21] CPP12 Cyclic(FXR4)
X: L-2-naphthylalanine [22] CPP2 DSLKSYWYLQKFSWR [23] CPP44 KRPTMRFRYTWNPMK [23] CPP9 Cyclic(fXRrRrQ)
X: L-2-naphthylalanine [24] Cyclic [W(RW)4] Cyclic[W(RW)4] [25] Cyclic R9 Cyclic(CRRRRRRRRR) [26] Cyt c77-101 GTKMIFVGIKKKEERADLIAYLKKA [27] D-Oligoarginine rn [28] D-Tat49-57 Rkkrrqrrr [28] DPV1047 VKRGLKLRHVRPRVTRMDV [29] DPV3 RKKRRRESRKKRRRES [29] dTat-Sar-EED4 rrrqrrkkrXXXXXXGWWG
X: Sar, sarcosine [30] FHV coat35-49 RRRRNRTRRNRRRVR [31] GALA WEAALAEALAEALAEHLAEALAEALEALAA [32] H5WYG GLFHAIAHFIHGGWHGLIHGWYG [33] HA2 GDIMGEWGNEIFGAIAGFLG [34] HAad IWLTALKFLGKAAAKAXAKQXLSKL
X: L-2-aminoadipic acid [35] hCT9-32-br LGTYTQDFNK(X)FHTFPQTAIGVGAP
X: PKKKRKVEDPGVGFA [36] HIV-1 Rev34-50 TRQARRNRRRRWRERQR [31] HL CHHHHHRRWQWRHHHHHC [37] HR9 CHHHHHRRRRRRRRRHHHHHC [38] HTLV-II Rex4-16 TRRQRTRRARRNR [31] Hydrophobic MPS VTVLAGALAGVGVG [39] K10H16 KKKKKKKKGHHHHHHHHHHHHHHHH [40] KAibA poly(KUA)
U: Aib, 2-aminoisobutyric acid [41] KALA WEAKLAKALAKALAKHLAKALAKALKACEA [42] KLA (KLAKLAK)2 [43] KLA10 KALKKLLAKWLAAAKALL [44] L-ProGu peptide (RRX)3
X: L-ProGu; 4-guanidinoproline [45] L1-7 Cyclic FIDIIIKILLI
Crosslink between the side chains of D and K [46] L17E IWLTALKFLGKHAAKHEAKQQLSKL [47] L6 RRWQWR [48] LAH4 KKALLALALHHLAHLALHLALALKKA [49] LAH4-L1 KKALLAHALHLLALLALHLAHALKKA [50] LH LHHLLHHLHHLLHH [51] LK LKKLLKLLKKLLKL [52] LTP RRKRRKKRRKRRKKKAC [53] M1 TFYGGRPKRNNFLRGIR [54] ... M918 MVTVLFRRLRIRRACGPPRVRV [55]
