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1.U.1.  The  Cationic Cell-penetrating Peptide (CCPP) Family

Cationic cell-penitrating peptides are usually rich in Arg and/or Lys and can penitrate cell membranes with or without assistance from other cellular proteins.  For example, cationic cell-penetrating peptide, PEP-NJSM, was identified in human virus proteomes by a screening of charge clusters in protein sequences generating Cell-Penetrating Peptides (CPP) (Mnif et al. 2019). PEP-NJSM was selectively active against Gram-positive Staphylococcus epidermidis as an antibacterial agent with a MIC value of 128 μM compared to the Gram-negative Pseudomonas aeruginosa strain with a MIC value exceeded 512 μM. The selected peptide, RYAKMKRRRRRVARRHRRR, exhibited an anti-biofilm activity at sub-MIC levels. PEP-NJSM prevent ed biofilm formation and increased the mortality of cells inside mature S. epidermidis biofilms and had anti-adherent activity. It showed S. epidermidis inhibition of biofilm formation >84% at a concentration of 256 μM (2 X MIC) and remained active even at a concentration of 4 μM with 32% inhibition. Eradication of an established biofilm was observed at a concentration of 256 μM with 56% biofilm eradication. PEP-NJSM exhibited low hemolytic activity and cytotoxicity against mammalian cells (Mnif et al. 2019).  Allolio et al. 2018 argued that the passive CCPP cell penetration mechanism bears analogy to vesicle fusion.

Battogtokh et al. 2018 directly conjugated mitochondrial-targeting moieties to anticancer drugs, antioxidants and sensor molecules. The most widely applied mitochondrial targeting moiety was triphenylphosphonium (TPP), which is a delocalized cationic lipid that readily accumulates and penetrates through the mitochondrial membrane due to the negative mitochondrial membrane potential. Other moieties, including short peptides, dequalinium, guanidine, rhodamine, and F16, are also promising mitochondrial targeting agents. Direct conjugation of mitochondrial targeting moieties to anticancer drugs, antioxidants and sensors resulted in increased cytotoxicity, anti-oxidizing activity and sensing activity, respectively, compared with their non-targeting counterparts, especially in drug-resistant cells.

The abundance of B cell lymphoma gene 2 (Bcl-2) correlates with the resistance of cancer cells to chemotherapeutic agents, but a peptide derived from orphan nuclear receptor Nur77 can convert Bcl-2 from a protector to a killer of cancer cells. Mesoporous silica nanoparticles (MSNs) can deliver small molecule drugs into cells. The effective encapsulation and intracellular delivery of peptides using small pore-sized MSNs has been achieved (Xu et al. 2018). Large-sized pore silica nanoparticles exhibited high Bcl-2-converting peptide-loading efficiency. The peptide inducedthe apoptotic status by penetrating the membranes of mitochondria and then being bound with Bcl-2 to expose the BH3 domain. 

CPPs can translocate across lipid bilayers and enter the lumen of a vesicle. Three models for the mechanisms and pathways by which CPPs translocate across lipid bilayers have been suggested (Islam et al. 2018): (A) through pores induced by CPPs, (B) through transient prepores, and (C) via formation of inverted micelles. Both the pathway of translocation and the efficiency of CPP entry depend on the lipid composition of the bilayer and the type of CPP. The interaction of CPPs with bacterial cells sometimes yield strong antimicrobial activities. There are two modes of action: CPPs can induce damage to the plasma membrane and thus increase permeability, or CPPs enter the cytosol of bacterial cells without damaging the plasma membrane. Budagavi et al. 2018 showed that Latarcin 1-derived cell-penetrating peptides have antifungal asctivities as well as cell-penetrating properties in Fusarium solani.


References associated with 1.U.1 family:

Allolio, C., A. Magarkar, P. Jurkiewicz, K. Baxová, M. Javanainen, P.E. Mason, R. Šachl, M. Cebecauer, M. Hof, D. Horinek, V. Heinz, R. Rachel, C.M. Ziegler, A. Schröfel, and P. Jungwirth. (2018). Arginine-rich cell-penetrating peptides induce membrane multilamellarity and subsequently enter via formation of a fusion pore. Proc. Natl. Acad. Sci. USA 115: 11923-11928. 30397112
Avgousti, D.C., C. Herrmann, K. Kulej, N.J. Pancholi, N. Sekulic, J. Petrescu, R.C. Molden, D. Blumenthal, A.J. Paris, E.D. Reyes, P. Ostapchuk, P. Hearing, S.H. Seeholzer, G.S. Worthen, B.E. Black, B.A. Garcia, and M.D. Weitzman. (2016). A core viral protein binds host nucleosomes to sequester immune danger signals. Nature 535: 173-177. 27362237
Battogtokh, G., Y.S. Choi, D.S. Kang, S.J. Park, M.S. Shim, K.M. Huh, Y.Y. Cho, J.Y. Lee, H.S. Lee, and H.C. Kang. (2018). Mitochondria-targeting drug conjugates for cytotoxic, anti-oxidizing and sensing purposes: current strategies and future perspectives. Acta Pharm Sin B 8: 862-880. 30505656
Budagavi, D.P., S. Zarin, and A. Chugh. (2018). Antifungal activity of Latarcin 1 derived cell-penetrating peptides against Fusarium solani. Biochim. Biophys. Acta. Biomembr 1860: 250-256. 29108892
Islam, M.Z., S. Sharmin, M. Moniruzzaman, and M. Yamazaki. (2018). Elementary processes for the entry of cell-penetrating peptides into lipid bilayer vesicles and bacterial cells. Appl. Microbiol. Biotechnol. 102: 3879-3892. 29523934
Mnif, S., M. Jardak, I. Graiet, S. Abid, D. Driss, and N. Kharrat. (2019). The novel cationic cell-penetrating peptide PEP-NJSM is highly active against Staphylococcus epidermidis biofilm. Int J Biol Macromol 125: 262-269. 30521892
Xu, W., P. Ge, B. Niu, X. Zhang, J. Liu, and J. Xie. (2018). Macroporous silica nanoparticles for delivering Bcl2-function converting peptide to treat multidrug resistant-cancer cells. J Colloid Interface Sci 527: 141-150. 29787950