Conformationally constrained peptides for drug delivery

Abstract

Peptides have shown great potential in acting as template for developing versatile carrier platforms in nanomedicine, aimed at selective delivery of drugs to only pathological tissues saving its normal neighbors. Cell‐penetrating peptides (CPPs) are short oligomeric peptides capable of translocating across the cell membrane while simultaneously employing multiple mechanisms of entry. Most CPPs exist as disordered structures in solution and may adopt a helical conformation on interaction with cell membrane, vital to their penetrative capability. Herein, we report a series of cationic helical amphipathic peptides (CHAPs), which are topologically constrained to be helical. The peptides were tested against cervical and breast cancer cells for their cell penetration and drug delivery potential. The cellular uptake of CHAP peptides is independent of temperature and energy availability. The activity of the peptides is biocompatible in bovine serum. CHAPs delivered functional methotrexate (MTX) inside the cell as CHAP‐MTX conjugates. CHAP‐MTX conjugates were more toxic to cancer cells than MTX alone. However, the CHAP‐MTX conjugates were less toxic to HEK‐293 cells compared with the cancer cells suggesting higher affinity towards cancer cells.

Studies of cell-penetrating peptides by biophysical methods

“…The best cargo deliverers were peptides composed of an equal number of Arg, Leu, and 1-aminocyclopentane-1-carboxylic acid; this peptide was retained in 310/ α -helical conformation. Another strategy to obtain helical CPPs is to synthesize topologically constrained amphipathic peptides that are unordered in solution but form a very stable α -helix when in contact with the membrane (Jerath et al ., 2020). These peptides are also analyzed by CD and with complementary methods.…”

New generation of cell‐penetrating peptides: Functionality and potential clinical application

“…For this reason, their N‐ and C‐terminus or peptide backbone can be modified by fatty acylation or amidylation, 78,79,129 and certain amino acid residues in their sequence can be replaced by residues in D configuration 23,109,110 or by nonproteinogenic amino acids and moieties 78,79,129,130 . For example, peptides can be cyclized through the formation of disulfide or lactam bridges, 48,49,65,76,130,131 or even by modification or cyclization of the peptide backbone 132–135 . Qian et al 117 tested even the oral bioavailability of an applied cyclic hexapeptide by studying time dependent plasma concentrations after oral administration.…”

Delivery of Small Molecules by Syndiotactic Peptides for Breast Cancer Therapy

“…The cells treated with peptides under standard conditions were taken as a reference for deducing the dependence of cellular uptake on temperature and energy availability. The details of the treatment procedure and conditions have been discussed in detail elsewhere …”

“…We have earlier demonstrated the use of nonproteogenic d -amino acids in 12-mer peptide sequences for their antimicrobial effects and cell penetration abilities. − The peptide design process adopted in the present study is two-dimensional, with the design of both the peptide backbone and amino acid side chain sequences. A syndiotactic stereochemical sequence (alternating l - and d - stereoisomers in a sequence, LDLD or DLDL) was chosen as the peptide backbone.…”

“…Electrostatics modulates the interactions of CPPs with the corresponding cell surface. Therefore, for the design of the amino acid side chain sequences, we reverse-engineered the spatial electrostatic potential distribution of the previously designed peptides with cell penetration ability. , The spatial electrostatic fingerprints of the earlier designed peptides were generated as described previously . The reverse-engineered sequences with a shorter (7-mer) chain length were compared to the previous designs through multiple iterations of amino acid sequences.…”