Cationic and amphipathic cell-penetrating peptides (CPPs): Their structures and <i>in vivo</i> studies in drug delivery

doi:10.1007/s11705-015-1538-y

Front. Chem. Sci. Eng.

2015, Vol. 9

Issue (4) : 407-427 https://doi.org/10.1007/s11705-015-1538-y

REVIEW ARTICLE

Cationic and amphipathic cell-penetrating peptides (CPPs): Their structures and in vivo studies in drug delivery

Jennica L. Zaro,Wei-Chiang Shen(

)

Department of Pharmacology and Pharmaceutical Science, University of Southern California, Los Angeles, CA 90033, USA

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Abstract

Over the past few decades, cell penetrating peptides (CPPs) have become an important class of drug carriers for small molecules, proteins, genes and nanoparticle systems. CPPs represent a very diverse set of short peptide sequences (10?30 amino acids), generally classified as cationic or amphipathic, with various mechanisms in cellular internalization. In this review, a more comprehensive assessment of the chemical structural characteristics, including net cationic charge, hydrophobicity and helicity was assembled for a large set of commonly used CPPs, and compared to results from numerous in vivo drug delivery studies. This detailed information can aid in the design and selection of effective CPPs for use as transport carriers in the delivery of different types of drug for therapeutic applications.

Keywords cell penetrating peptides amphipathic peptides drug delivery

Corresponding Author(s): Wei-Chiang Shen

Online First Date: 04 November 2015 Issue Date: 26 November 2015

Cite this article:

Jennica L. Zaro,Wei-Chiang Shen. Cationic and amphipathic cell-penetrating peptides (CPPs): Their structures and in vivo studies in drug delivery[J]. Front. Chem. Sci. Eng., 2015, 9(4): 407-427.

URL:

https://academic.hep.com.cn/fcse/EN/10.1007/s11705-015-1538-y
https://academic.hep.com.cn/fcse/EN/Y2015/V9/I4/407

Sequence	Peptide name	Origin	%^a)	NC^b)	Helical^c)	Ref.
Protein derived CPPs
GRKRKKRT	6-Oct	Transcription factor Oct-6	0%	+6	No	[11,12]
RRIRPRPPRLPRPRP	Bac-1-15	Bactenecin 7	13%	+7	No	[13]
KMDCRWRWKCCKK	Crot (27?39)	Rattlesnake venom (Crotamine)	46%	+5	No	[14]
RKKRRRESRKKRRRES	DPV3	Human superoxide dismutase	0%	+12	No	[15]
RRRRNRTRRNRRRVRGC	FHV coat (35?49)	RNA binding peptides	11%	+11	No	[16−18]
ASMWERVKSIIKSSLAAASNI	FHV γ peptide	Flock house virus	52%	+2	Yes (8 THR)	[19,20]
LGTYTQDFNKFHTFPQTAIGVGAP	hCT (9?32)	Human calcitonin (hCT)	33%	0	No	[21]
GGVCPKILKKCRRDSDCPGACICRGNGYCGSGSD	MCoTI-II(MCo)	Momordica cochinchinensis trypsin inhibitor II	32%	+3	No	[22]
VQRKRQKLMP	NF-kB	Transcription factor NF-kB	30%	+4	No	[12]
NAKTRRHERRRKLAIERGC	P22 N	RNA binding peptides	26%	+6	No	[16]
RQIKIWFQNRRMKWKK	Penetratin (Antp)	Antennapedia homeodomain of drosophila	37%	+7	Yes (3 THR)	[14,20,21,23−33]
LLIILRRRIRKQAHAHSK	pVEC	Murine vascular endothelial-cadherin protein	44%	+6	Yes (4 THR)	[34]
PKKKRKV	SV40	Transcription factor SV40	14%	+5	No	[12]
RRLSYSRRRF	SynB3	Protegrin	30%	+5	No	[31]
GRKKRRQRRRPPQC	HIV-1 Tat (47?57)	HIV-1	7%	+8	No	[13−15,17,21,29,33,35−43]
VSRRRRRRGGRRRR	LMWP	Protamine	7%	+10	No	[44]
KAAPAKKAAAKKAPAKKAAAKK	HBHAc	Mycobacteriumtuberculosis	44%	+10	No	[45]
Chimeric CPPs
CHHHHHRKKRRQRRRHHHHHC	mTat	Tat+ histidine	5%	+6	No	[46]
KETWWETWWTEWSQPKKKRKV	Pep-1	Trp rich cluster+ SV40 NLS	28%	+3	Yes (5 THR)	[47]
KETWFETWFTEWSQPKKKRKV	Pep-2	Trp rich cluster+ SV40 NLS	28%	+3	Yes (5 THR)	[48]
KWFETWFTEWPKKRK	Pep-3	Trp rich cluster+ SV40 NLS	33%	+3	Yes (3 THR)	[48]
PKKKRKVALWKTLLKKVLKA	PV-S4(13)	SV40 NLS+ dermaseptin S4 peptide	45%	+9	Yes (7 THR)	[40]
AAVALLPAVLLALLAPVQRKRQKLMP	SN50	Signal sequence of K-FGF+ NLS of NF-kB p50 subunit	65%	+4	Yes (6 THR)	[49]
AGYLLGKINLKALAALAKKIL	Transportan; TP10	Fusion of neuropeptide galanin and wasp venom peptide	61%	+4	Yes (9 THR)	[26,29,50]
Synthetic CPPs
WEAALAEALAEALAEHLAEALAEALEALAA	GALA	n/a	73%	?7	Yes(17 THR)	[51]
IRQRRRR	IRQ	n/a	29%	+5	No	[52]
WEAKLAKALAKALAKHLAKALAKALKACEA	KALA	n/a	66%	+5	Yes(16 THR)	[53]
KLALKLALKALKAALKLA	MAP	n/a	72%	+5	Yes(12 THR)	[28,54,55]
l-R_n, d-R_n (n = 5?16)	Oligoarginine	n/a	0%	+n	No	[14,16,23,29,30,35,41,42,55−58]
RALARALARALRALAR	RALA	n/a	69%	+5	No	[59]
WRWRWRWRWRWRWR	RW	n/a	50%	+7	No	[18]
CVQWSLLRGYQPC	S41	n/a	46%	+1	No	[60]

Tab.1 Examples of CPPs

Fig.1 Guanidine structure in CPPs. (A) Structural comparison of arginine and lysine side chains, along with guanidinated (Gnd)-lysine and methylated arginine; (B) Proposed hydrogen bonding of the guanidine group of arginine with phosphate groups present at the cell surface

Tab.2 Comparison of CPPs for cytosolic versus vesicular accumulation

Fig.2 Proposed mechanisms of internalization. Endocytic internalization mechanisms including (1) macropinocytosis, (2) micropinocytosis, (3) clathrin-mediated endocytosis, and (4) caveolar-mediated endocytosis have been shown to be involved in CPP uptake into cells. Several endocytosis-independent mechanisms have also been proposed, including membrane destabilization through (5) inverted micelle formation, or the (6) “carpet” model describing perturbation of the phospholipids to increase membrane fluidity; or pore formation through (7) membrane insertion following interaction with the anionic groups of the phospholipid membrane to form toroidal pores, or (8) formation of an α-helical structure within the membrane where hydrophilic side chains form the inner face of the port to form a barrel stave pore.

Tab.3 CPP-small molecule conjugates for in vivo delivery^a)

Fig.3 Examples of linkers in small molecule-CPP conjugates. Stable linkers for small-molecule CPPs include the thioether linkage, which is achieved utilizing a maleimido-reactive group, the triazole linker by use of copper-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) click chemistry, and the amide linkage using carbodiimides and/or N-hydroxysuccinimide esters. Cleavable linkers include those cleaved in acidic pH such as the hydrazone linker, obtained by reaction of an aldehyde with a hydrazide, and the cis-aconityl linker, obtained by reaction of citraconic anhydride with an amine. Disulfide linkers formed between two thiols, which are cleaved under reducing conditions are also used.

Fig.4 Examples of masking strategies to target CPP-drug delivery systems. Due to their high cationic charge, CPPs are non-specifically internalized in many types of cells and tissues. This non-specific distribution can overpower the targeting recognition when combined with other active targeting approaches. One approach in overcoming this issue is by shielding the charge of the CPP until the complex reaches the target site. (A) In this example, the cationic charge of oligoarginine was masked by linkage to oligoglutamic acid through a protease-sensitive peptide sequence [124,125,131,137,154,155], or a hydrogen peroxide sensitive group [126]. Upon cleavage, the oligoarginine and oligoglutamic acid dissociate, revealing the cationic charge of oligoarginine. (B) Alternatively, the cationic charge of the CPP was masked by linkage to a histidine-glutamic acid copolymer sequence [122,123,157]. At physiological pH 7.4, the histidine is neutral while the glutamic acid is negative; therefore the net anionic copolymer masks the cationic charge of the CPP. With cationic histidine and anionic glutamic acid at mildly acidic pH 6.5?7, the copolymer net charge is neutral, unmasking cationic charge of the CPP. (C) In this example, the small chain PEG-CPPs are linked to lipids in a liposome via a stable linkage, and also targeted by conjugation with a long chain PEG-antibody via a cleavable linker (e.g., protease sensitive [158] or acidic pH-labile [159]). In this design, the CPP conjugated to a small PEG chain is masked by the longer PEG chain linked to a targeting agent. Once the liposomes accumulate near the surface of the target site, the targeting agent-long PEG chain conjugate is cleaved, revealing the CPP to drive the internalization

CPP	% Φ	NC	Helical^b)	Drug /cargo	Delivery system	Studies	Animal model	Ref.
Tat	7%	+8	No	Gelonin	Tat-gelonin+ CEA-heparin complex	Tumor targeting & reduction	Mouse (LS174T xenograft)	[167]
Tat	7%	+8	No	HaFGF	Fusion protein	Intranasal delivery	Rat	[168]
R₈-linker-E₈ (linker: cleavable by MMP2)	0%	+8	No	MMAE	Fusion protein with integrin targeting cyclic peptide	Tumor regression	Mouse (mDA-MB-231 xenograft)	[154]
Tat	7%	+8	No	β-galactosidase	Fusion protein	PK; tissue distribution	Mouse	[169]
Tat	7%	+8	No	BCL6 peptide inhibitor	Fusion protein	Tissue penetration; tumor regression	Mouse (DLBCL xenograft)	[170]
Penetratin	37%	+7	Yes	p53(17?26)	Fusion protein	Tumor regression	Mouse (TUC-3 xenograft)	[171]
Tat	7%	+8	No	[(KLAKLAK)₂-DEVD]₃	Fusion protein	Apoptosis at tumor site	Mouse (B16-F10 xenograft)	[172]
Tat	7%	+8	No	AHPN	Fusion protein	Tumor growth inhibition	Mouse (435.eB xenografts)	[173]
Penetratin	37%	+7	Yes	NBD peptide	Fusion protein	Anti-inflammatory effect	Colitis-induced mouse model	[174]
Penetratin	37%	+7	Yes	NBD peptide	Fusion protein	Prevention of nigrostriatal degeneration	Parkinson’s disease mouse model	[175]
Tat	7%	+8	No	BH4 peptide	Fusion protein	Immunosupression	Mouse sepsis model	[176]
Tat	7%	+8	No	STAT-6-IP	Fusion protein	Inhibition of lung inflammation	Allergic rhinitis and asthma mouse model	[177]
d-R9	0%	+9	No	Insulin	Fusion protein	Decreased blood glucose levels	Diabetic rat model	[41]
(HE)₁₀-MAP-GST	72%	+5	Yes	GST	Fusion protein	Tumor targeting	Mouse (MDA-MB-231 xenograft)	[122]
Bac	13%	+7	No	p21 peptide	ELP-fusion protein	Tumor targeting; survival time	Mouse (S2013 xenograft)	[178]
d-Tat	7%	+8	No	AlexaFluor-488 (fluorophore), QSY7 (quencher)	Fusion peptide with activatable probe containing DEVD sequence	Imaging of caspase activity	Rat	[179]
Pep-1	28%	+3	Yes	HO-1	Fusion protein	Prevention of intestinal ischemia	Rat	[180]
Pep-1	28%	+3	Yes	HO-1	Fusion protein	Reduced myocardial infarct size	Ischemic rats	[181]

Tab.4 CPP-fusion proteins for in vivo delivery^a)

Tab.5 Non-covalent CPP-complexes for in vivo delivery^a)

Fig.5 Poly-L-lysine (PLL)-CPP siRNA Polyplexes. In order to overcome the issue of charge neutralization of the CPP upon complexation with siRNA, a multi-component polyplex consisting of siRNA, 21mer PLL modified to incorporate CPP conjugation sites, and a CPP was designed. PLL was first reacted with the amine-to-thiol crosslinker, N-succinimidyl 3-(2-pyridyldithio) propionate to form pyridyldithiol (PDP)-activated PLL, and then complexed with siRNA to form a neutral polyplex. Cysteine-terminal CPPs were then conjugated to the siRNA-polyplex via a reducible disulfide bond in order to allow for separation of the carrier CPPs from the PLL-siRNA polyplex following access to the reductive cytosolic compartment [190]

Tab.6 CPP-modified Nanoparticles for in vivo delivery^a)

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