Hybrid Cyclic-Linear Cell-Penetrating Peptides Containing Alternative Positively Charged and Hydrophobic Residues as Molecular Transporters

Shoushtari, Sorour Khayyatnejad; Zoghebi, Khalid; Sajid, Muhammad Imran; Tiwari, Rakesh; Parang, Keykavous

doi:10.1021/acs.molpharmaceut.1c00594

Cited by 6 publications

(13 citation statements)

References 29 publications

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“…Recently, cyclic linear hydrid peptides containing alternately Arg and Trp residues have been developed, as described in the text. Their transport efficiency of molecules for therapeutic purposes such as anti-HIV drugs with short incubation time has been demonstrated (Khayyatnejad Shoushtari et al ., 2021).…”

Section: Discussionmentioning

confidence: 99%

Tryptophan, more than just an interfacial amino acid in the membrane activity of cationic cell-penetrating and antimicrobial peptides

Khemaissa

Walrant

Sagan

2022

Quart. Rev. Biophys.

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Trp is unique among the amino acids since it is involved in many different types of noncovalent interactions such as electrostatic and hydrophobic ones, but also in π-π, π-cation, π-anion and π-ion pair interactions. In membranotropic peptides and proteins, Trp locates preferentially at the water-membrane interface. In antimicrobial or cell-penetrating peptides (AMPs and CPPs respectively), Trp is well-known for its strong role in the capacity of these peptides to interact and affect the membrane organisation of both bacteria and animal cells at the level of the lipid bilayer. This essential amino acid can however be involved in other types of interactions, not only with lipids, but also with other membrane partners, that are crucial to understand the functional roles of membranotropic peptides. This review is focused on this latter less known role of Trp and describes in details, both in qualitative and quantitative ways: (i) the physico-chemical properties of Trp; (ii) its effect in CPP internalisation; (iii) its importance in AMP activity; (iv) its role in the interaction of AMPs with glycoconjugates or lipids in bacteria membranes and the consequences on the activity of the peptides; (v) its role in the interaction of CPPs with negatively charged polysaccharides or lipids of animal membranes and the consequences on the activity of the peptides. We intend to bring highlights of the physico-chemical properties of Trp and describe its extensive possibilities of interactions, not only at the well-known level of the lipid bilayer, but with other less considered cell membrane components, such as carbohydrates and the extracellular matrix. The focus on these interactions will allow the reader to reevaluate reported studies. Altogether, our review gathers dedicated studies to show how unique are Trp properties, which should be taken into account to design future membranotropic peptides with expected antimicrobial or cell-penetrating activity.

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Section: Discussionmentioning

confidence: 99%

Tryptophan, more than just an interfacial amino acid in the membrane activity of cationic cell-penetrating and antimicrobial peptides

Khemaissa

Walrant

Sagan

2022

Quart. Rev. Biophys.

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“…They can transport small molecules that cannot penetrate through the cell membrane inside the cell. − These peptides use energy-independent and energy-dependent pathways to penetrate the cell membrane . CPPs are used in different ways to mediate cellular cargo delivery, which are covalent conjugating with the cargo − or creating stable noncovalent − complexes. Some of these peptides can penetrate the cell without generating significant cytotoxicity.…”

Section: Introductionmentioning

confidence: 99%

“…Our previous studies showed that cyclic CPPs, [WR] 4 and [WR] 5 , with alternation of tryptophan (W) and arginine (R) residues, increased the cellular uptake of different compounds such as phosphopeptides, doxorubicin, ,,, paclitaxel, camptothecin, curcumin, , anti-HIV drugs, , gadolinium nanoparticles, selenium nanoparticles, gold nanoparticles, , and oligonucleotides. , Cyclic CPPs containing alternate W and R residues demonstrated improved cellular uptake delivery when compared to linear CPPs . Moreover, the uptake of both [WR] 4 and [WR] 5 was not dependent on the endocytosis pathway. , …”

Section: Introductionmentioning

confidence: 99%

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Cyclic and Linear Peptides Containing Alternate WW and RR Residues as Molecular Cargo Delivery Tools

et al. 2022

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Cell-impermeable and negatively charged compounds' cellular uptake across the cell membranes remains challenging. Herein, the synthesis of four linear [(WWRR) 2 , (WWRR) 3 , (WWRR) 4 , and (WWRR) 5 ] and four cyclic ([WWRR] 2 , [WWRR] 3 , [WWRR] 4 , and [WWRR] 5 ) peptides containing alternate two tryptophan (WW) and two arginine (RR) residues and their biological evaluation as molecular transporters are reported. The peptides did not show any significant cytotoxicity in different cell lines (MDA-MB-23, SK-OV-3, and HEK 293) at a concentration of 5 μM and after 3 h of incubation time. The uptake of fluorescence-labeled cargo molecules (F′-GpYEEI, F′-siRNA, and F′-3TC) in the presence of the peptides was monitored in different cell lines (SK-OV-3 and MDA-MB-231) with fluorescence-activated cell sorting. Among all the peptides, [WWRR] 5 (C4) showed the highest cellular uptake of cargo molecules, indicating it can act as effective molecular transporter. Confocal microscopy in MDA-MB-231 cells showed the cellular uptake of F′-GpYEEI in the presence of C4 and the intracellular localization of fluorescence-labeled C4 (F′-C4) in the cytosol. The F′-C4 cellular uptake was found to be concentration-and time-dependent, as shown by flow cytometry in MDA-MB-231 cells. Confocal microscopy and flow cytometry of F′-C4 in MDA-MB-231 cells were examined alone and in the presence of different endocytosis inhibitors (chlorpromazine, methyl-β-cyclodextrin, chloroquine, and nystatin). The data showed that the cellular uptake of F′-C4 in the presence of chlorpromazine, chloroquine, and methyl-β-cyclodextrin was reduced but not completely eliminated, indicating that both energy-independent and energy-dependent pathways contributed to the cellular uptake of F′-C4. Similar results were obtained using the confocal microscopy of C4 and F′-GpYEEI in the presence of endocytosis inhibitors (chlorpromazine, methyl-β-cyclodextrin, chloroquine, and nystatin). These data indicate that C4 has the potential to be used as a cell-penetrating peptide and cargo transporter.

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“…The study demonstrated that uptake of the cargo was not only dependent on the CPP, it was conjugated too, but also on the cell line it was tested in, including HeLa, HEK, and HepG2 [ 30 ]. Khayyatnejad et al utilized a hybrid cyclic-linear CPP, ((RW) 5 )K(RW) X , to transport two different cargoes: a phosphopeptide and an anti-HIV drug [ 31 ]. While the goal of this study was to determine how the addition of positive and hydrophobic residues to the linear chain of the CPP affected uptake, it also demonstrated there was a significantly different uptake of these two different CPP/cargo complexes.…”

Section: Introductionmentioning

confidence: 99%

How Cargo Identity Alters the Uptake of Cell-Penetrating Peptide (CPP)/Cargo Complexes: A Study on the Effect of Net Cargo Charge and Length

Hymel

Rahnama

Sánchez

et al. 2022

Cells

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Cell-penetrating peptides (CPPs) have emerged as a powerful tool for the delivery of otherwise impermeable cargoes into intact cells. Recent efforts to improve the delivery capability of peptides have mainly focused on the identity of the CPP; however, there is evidence that the identity of the cargo itself affects the uptake. The goal of this work was to investigate how the characteristics of a peptide cargo, including net charge and length, either enhance or diminish the internalization efficiency of the CPP/cargo complex. A small library of CPP/cargo complexes were synthesized consisting of structured and unstructured CPPs with cargoes of net positive, negative, or neutral charge and lengths of 4 or 8 amino acids. Cargoes with a net positive charge were found to enhance the overall uptake of the complexes while net neutral and negatively charged cargoes diminished uptake. Conversely, the net length of the cargo had no significant effect on uptake of the CPP/cargo complexes. Microcopy images confirmed the increased uptake of the positively charged cargoes; however, an increase in punctate regions with the addition of a cargo was also observed. The effects of the net positively charged cargoes were confirmed with both structured and unstructured CPPs, which demonstrated similar trends of an increase in uptake with the addition of positively charged residues. These findings demonstrate that the net charge of cargoes impacts the uptake of the complex, which can be considered in the future when designing peptide-based reporters or therapeutics.

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Hybrid Cyclic-Linear Cell-Penetrating Peptides Containing Alternative Positively Charged and Hydrophobic Residues as Molecular Transporters

Cited by 6 publications

References 29 publications

Tryptophan, more than just an interfacial amino acid in the membrane activity of cationic cell-penetrating and antimicrobial peptides

Tryptophan, more than just an interfacial amino acid in the membrane activity of cationic cell-penetrating and antimicrobial peptides

Cyclic and Linear Peptides Containing Alternate WW and RR Residues as Molecular Cargo Delivery Tools

How Cargo Identity Alters the Uptake of Cell-Penetrating Peptide (CPP)/Cargo Complexes: A Study on the Effect of Net Cargo Charge and Length

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