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The present work describes the synthesis, characterization, and wound healing properties of α/γ hybrid peptides: Boc-Phe-γ 4 -Phe-Val-OMe (S1), Boc- D Phe-γ 4 -Phe-Val-OMe (S2), Boc-Ala-γ 4 -Phe-Val-OMe (S3), Boc- D Ala-γ 4 -Phe-Val-OMe (S4), Boc-Leu-γ 4 -Phe-Val-OMe (S5), and Boc- D Leu-γ 4 -Phe-Val-OMe (S6). Peptides S1-S6 were screened against human keratinocytes (HaCaT) and RAW 264.7 cells. Among all, S1- and S2-treated cells exhibited high cell viability; S1 and S2 induced keratinocyte migration and inhibited the production of the cytokines IL-6 and TNF-α. In vivo results demonstrated that the hybrid peptides S1 and S2 accelerate wound healing in Wistar rats with 83% and 88% at 50 μg/ml, and 74% and 76% at 25 μg/ml, respectively., (© 2023 European Peptide Society and John Wiley & Sons Ltd.)

The present work describes the synthesis and characterization of α/γ hybrid peptides, Boc-Phe-γ 4 -Phe-Val-OMe, P1; Boc-Ala-γ 4 -Phe-Val-OMe, P2; and Boc-Leu-γ 4 -Phe-Val-OMe, P3 together with the formation of self-assembled structures formed by these hybrid peptides in dimethyl sulfoxide (DMSO)/water (1:1). The self-assembled structures were characterized by infrared (IR) spectroscopy, circular dichroism (CD), and scanning electron microscopy (SEM). Further, α/γ hybrid peptide self-assembled structures were evaluated for antibacterial properties. Among all, the self-assembled peptide P1 exhibited the antimicrobial activity against Escherichia coli and Klebsiella pneumoniae, while self-assembled peptide P3 inhibited the biofilms of Salmonella typhimurium and Pseudomonas aeruginosa. In this study, we have shown the significance of self-assembled structures formed from completely hydrophobic α/γ hybrid peptides in exploring the antibacterial properties together with biofilm inhibition., (© 2020 European Peptide Society and John Wiley & Sons, Ltd.)

The present work describes the conformation of achiral α/β hybrid peptides, Boc‐Gly‐β3,3‐Ac6c‐NHMe (P1), Boc‐Gly‐β3,3‐Ac6c‐Gly‐OMe (P2), and Boc‐Gly‐β3,3‐Ac6c‐Gly‐β3,3‐Ac6c‐OMe, (P3) using X‐ray crystallography. Peptides P1 and P2 adopt C11 and C12 folded conformations, respectively. The directionality of the hydrogen bond observed in P1 is opposite to that observed in peptide P2. In case of tetrapeptide P3, no such hydrogen bond is observed. Further, the solvent titration experiment establishes the similar intramolecular hydrogen bonding as observed in the crystals. In P1 and P2, the amino group of β3,3‐Ac6c occupies equatorial orientations, while in the case of peptide P3, it occupies axial and equatorial orientations for residues β3,3‐Ac6c(2) and β3,3‐Ac6c(4), respectively. The average (ϕ,θ,ψ) torsional preferences of β3,3‐Ac6c in achiral α/β peptides are somewhat different from that of chiral α/β peptides. [ABSTRACT FROM AUTHOR]

The current work demonstrates the synthesis and characterization of piperic acid conjugates with homochiral/heterochiral dipeptides containing phenylalanine as anti-skin cancer agents. The conjugates PA-DPhe-LPhe-OH, FC-1 ; PA-LPhe-DPhe-OH, FC-2 ; PA-DPhe-DPhe-OH, FC-3 ; and PA-DPhe-DPhe-OH, FC-4 were synthesized, characterized and assessed for cytotoxicity against melanoma cell lines of human and murine origin. Among all, PA-DPhe-DPhe-OH (FC-3) conjugate was identified as a potential cytotoxic lead against melanoma cells by delineating the anti-proliferative and anti-migratory potential together with its anti-inflammatory potential against pro-inflammatory interleukins (IL-1β, IL-6, and IL-8). Evidences from western blotting, fractionation, and immunocytochemistry experiments suggest that Stat-3 is a critical signaling molecule involved in the FC-3 mechanism of action. The results denote that FC-3 profoundly ablates Stat-3 expression, phosphorylation, and nuclear translocation. Stat-3 mRNA analysis revealed that FC-3 did not alter the transcription of Stat-3. However, in cells where proteasome mediated degradation was inhibited, FC-3 failed to check the Stat-3 expression implying that FC-3 augments the proteasomal degradation of Stat-3. Of note, FC-3 failed to reverse the IL-6 mediated hyperactivation of Stat-3 in A375 cells. Critically, in Stat-3 deficient cancer cells, the anti-clonogenic and anti-migratory potential of FC-3 was significantly subdued. Further, the in vivo efficacy of FC-3 was validated in the two-step (DMBA/TPA) chemically induced mouse skin cancer model. The FC-3 -treated cohorts of mice unveiled a significant decrease in the cumulative number of tumors besides attenuation of tumor growth with respect to the vehicle-treated mice. Lastly, in corroboration with our in vitro findings, serum collected from mice groups at various intervals during the treatment regimen demonstrated decrement in IL-1β and IL-6 levels in FC-3 treated groups compared to the vehicle-treated group. [Display omitted] • Piperic acid conjugates with homochiral/heterochiral dipeptides, PA-DPhe-LPhe-OH, FC-1 ; PA-LPhe-DPhe-OH, FC-2 ; PA-DPhe-DPhe-OH, FC-3 ; and PA-DPhe-DPhe-OH, FC-4 , were synthesized and screened for cytotoxic potential against melanoma. • FC-3 mitigates the clonogenic, migratory, and inflammatory propensity of melanoma cells. • FC-3 ablates Stat-3 expression, phosphorylation, and nuclear translocation in melanoma cells. • In vivo efficacy of FC-3 was validated in the two-step (DMBA/TPA) chemically induced mouse skin cancer model. [ABSTRACT FROM AUTHOR]

The present work describes the synthesis,conformation and cytotoxic activities of short β/γ hybrid peptides, Boc-β2,2-Ac 6 c-Gpn-NHMe, BG1 ; Boc-(β2,2-Ac 6 c-Gpn) 2 -OMe, BG2 ; Boc-(β2,2-Ac 6 c-Gpn) 3 -OMe, BG3 ; H-β2,2-Ac 6 c-Gpn-NHMe, BG4 ; H-(β2,2-Ac 6 c-Gpn) 2 -OMe, BG5; H-(β2,2-Ac 6 c-Gpn) 3 -OMe, BG6, Boc-β2,2-Ac 6 c-Gpn-OMe, BG7 and H-β2,2-Ac 6 c-Gpn-OMe, BG8. Mixed C 6 /C 7 conformations were observed for β/γ hybrid peptides. Further, BG1 - BG8 were screened against MCF-7 (Breast cancer), A549 (Lung Cancer), PC-3 (Prostate cancer), HCT-116 (Colon cancer), and MDA-MB-231 (Breast cancer) cell lines. Among all, BG6 exhibited potent cytotoxicity against all cancer cell lines with IC 50 ranging from 1.6 μM to 6.3 μM with relatively low cytotoxicity against normal epithelial breast cell line fR-2 and human embryonic kidney cell line HEK-293. Minimal hemolytic activity was observed for BG6 against human erythrocytes. Peptide BG6 displayed anti-migratory and anti-invasive potentials showing strong interactions with intrinsic apoptotic markers Bcl-2, Bax, and cleaved-PARP, as well as the induction of the mitochondria maladjustment mediated apoptosis. [Display omitted] • Short β/γ hybrid peptides containing conformationally constrained amino acids exhibited C 6 /C 7 conformation. • Hybrid peptides BG1-BG8 were screened against MCF-7 (Breast cancer), A549 (Lung Cancer), PC-3 (Prostate cancer), HCT-116 (Colon cancer), and MDA-MB-231 (Breast cancer). • BG6 exhibited potent anticancer activity with IC 50 1.619 μM and 2.251 μM against MCF-7 and HCT-116, respectively. • BG6 showed anti-proliferative, antimigratory and anti-invasive potentials. • BG6 showed strong interactions with Bcl-2, Bax, and cleaved-PARP together with the induction of the mitochondria maladjustment mediated apoptosis. [ABSTRACT FROM AUTHOR]