Mono- and Co-Doped Mn-Doped CsPbCl3 Perovskites with Enhanced Doping Efficiency and Photoluminescent Performance.

To investigate the effect of Mn and other metal dopants on the photoelectronic performance of CsPbCl3 perovskites, we conducted a series of theoretical analyses. Our findings showed that after Mn mono-doping, the CsPbCl3 lattice contracted and the bonding strength increased, resulting in a more compact structure of the metal octahedral cage. The relaxation of the metal octahedral cage, along with the Jahn-Teller effect, results in a decrease in lattice strain between the octahedra and a reduction in the energy of the entire lattice due to the deformation of the metal octahedron. These three factors work together to reduce intrinsic defects and enhance the stability and electronic properties of CsPbCl3 perovskites. The solubility of the Mn dopant is significantly increased when co-doped with Ni, Fe, and Co dopants, as it compensates for the lattice strain induced by Mn. Doping CsPbCl3 perovskites reduces the band gap due to the decreased contributions of 3d orbitals from the dopants. Our analyses have revealed that strengthening the CsPbCl3 lattice and reducing intrinsic defects can result in improved stability and PL properties. Moreover, increasing Mn solubility and decreasing the bandgap can enhance the PLQY of orange luminescence in CsPbCl3 perovskites. These findings offer valuable insights for the development of effective strategies to enhance the photoelectronic properties of these materials.

Constructing new acid-activated anticancer peptide by attaching a desirable anionic binding partner peptide.

Improving the cell selectivity of anticancer peptides (ACPs) is a major hurdle in their clinical utilisation. In this study, a new acid-activated ACP was designed by conjugating a cationic ACP LK to its anionic binding partner peptide (LEH) via a disulphide linker to trigger antitumor activity at acidic pH while masking its killing activity at normal pH. Three anionic binding peptides containing different numbers of glutamic acid (Glu) and histidine were engineered to obtain an efficient acid-activated ACP. The conjugates LK-LEH2 and LK-LEH3 exhibited 6.1- and 8.0-fold higher killing activity at pH 6.0 relative to at pH 7.4, respectively, suggesting their excellent pH-dependent antitumor activity; and their cytotoxicity was 10-fold lower than that of LK. However, LK-LEH4 had no pH-responsive killing effect. Interestingly, increasing the number of Glu from 2 to 4 increased the pH-response of the physical mixture of LK and LEH; conversely, they weakly decreased the cytotoxicity of LK, suggesting that the conjugate connection is required to achieve excellent pH dependence while maintaining minimum toxicity. LK-LEH2 and LK-LEH3 were more enzymatically stable than LK, indicating their potential for in vivo application. Our work provided a basis for designing promising ACPs with good selectivity and low toxicity.

New designed pH-responsive histidine-rich peptides with antitumor activity.

Anticancer peptides have received widespread attention as alternative antitumor therapeutics due to their unique action mode. However, the systemic toxicity hampers their successful utilisation in tumour therapy. Here, the tumour acidic environment was used as a trigger to design a series of histidine-rich peptides by optimising the distribution of histidine and leucine based on the amphiphilic peptide LK, in hoping to achieve desirable acid-activate anticancer peptides. Among all the obtained peptides, L9H5-1 showed enhanced antitumor activity at acidic pH concomitant with low toxicity at normal pH, exhibiting excellent pH-response. At acidic pH, protonated L9H5-1 could rapidly kill tumour cells by efficient membrane disruption as evidenced by in vitro experiments, including increasing intracellular PI uptake and LDH release, dramatic membrane damage and increase of later apoptotic/necrotic cells. Moreover, no cell cycle arrest was observed after treated with L9H5-1. Interestingly, this study found that the new peptides with the same number of histidines and leucines displayed different pH-dependent antitumor activity, indicating that the position of amino acid alteration is extremely important for the design of acid-activated histidine-rich peptides. In short, our work provides a new avenue to develop new acid-activated anticancer peptides as promising antitumor drugs with high efficiency and good selectivity.

Newly designed antimicrobial peptides with potent bioactivity and enhanced cell selectivity prevent and reverse rifampin resistance in Gram-negative bacteria.

The increasing prevalence of antibiotic resistance in Gram-negative bacteria calls for the discovery of novel effective therapeutic strategies urgently. Mastoparan-C (MP-C), a typical cationic α-helical antimicrobial peptide, possesses remarkable broad-spectrum antimicrobial activity. However, its high cytotoxicity toward normal mammalian cells precludes it for further development. In this study, to avoid non-specific membrane lysis and investigate the structure-function relationships of each amino acid of MP-C, a series of new MP-C analogs were rationally designed by amino acid substitution and peptide truncation. Three potential newly designed peptides L1G, L7A, and L1GA5K with excellent bioactivity, modest cell toxicity, low resistance tendency, and moderate stability to physiological salts and proteases were screened out. Moreover, the newly designed peptides showed synergy or additive effects against Gram-negative bacteria, when they combined with conventional antibiotics gentamicin, rifampin, and polymyxin B. The results from the time-kill kinetics, outer/inner membrane permeabilization, scanning electron microscope (SEM), and flow cytometry demonstrated that the newly designed peptides could kill bacteria rapidly by membrane destruction and intracellular contents leakage in a concentration and time-dependent manner. Specifically, the most cell-selective peptide L1GA5K exhibited potent antimicrobial activity against rifampin-resistant E. coli (RRE) and prevented the emergence of rifampin resistance in Enterobacter. Besides, L1GA5K was capable of reversing rifampin resistance in RRE through the outer membrane permeabilization when used in combination with rifampin. Collectively, our results suggested that the newly designed peptides are hopeful antibiotic alternatives, and the usage of them as an adjuvant to prevent and reverse antibiotic resistance is a promising strategy for tackling the risk of drug-resistant Gram-negative bacteria.

Effect of N-methylated and fatty acid conjugation on analogs of antimicrobial peptide Anoplin.

With the increment of drug-resistant bacteria and the slow development of novel antibiotics, antimicrobial peptides have gained increasing attention as a potential antibiotic alternative. They not only displayed a broad-spectrum antimicrobial activity but also were difficult to induce resistance development because of their unique membrane-lytic activity. Herein, to improve the limitations of Anoplin, the N-methyl amino acids were first used to replace the amino acids of Anoplin at sensitive enzymatic cleave sites (Leu, Ile, Lys and Arg). Afterward, the N-methylated analogs M3.6/M4.7/M5.7 with high stability were screened out and further modified by N-terminal fatty acid conjugation to develop new antimicrobial peptide analogs with both potent antimicrobial activity and high proteolytic stability, and 12 new Anoplin analogs Cn-M3.6/M4.7/M5.7 (n = 8,10,12,14) were designed and synthesized. Our results showed that compared with native Anoplin, the stability of these N-methylated lipopeptides against trypsin and chymotrypsin degradation were increased by 104-106 times. Besides, they still possessed potent antimicrobial activity under physiological salts and serum environment. Among them, the new designed analogs C12-M3.6/M4.7/M5.7 showed the optimal antimicrobial activity, synergy and additive effects were also observed when they were combined with traditional antibiotics polymyxin B, rifampin, and kanamycin. Moreover, they could effectively inhibit the formation of biofilms by P. aeruginosa and S. aureus. The antimicrobial mechanism studied revealed that these N-methylated lipopeptides could display a rapid bactericidal effect by destroying the bacterial cell membrane. Notably, no detectable resistance of these new designed peptides was developed after continuous cultured with E. coli for 20 passages. In summary, we have designed a new class of antimicrobial peptide analogs with potent antimicrobial activity and high proteolytic stability through N-methyl amino acids substitution and N-terminal fatty acid conjugation. This study also provides new ideas and methods for the modification of antimicrobial peptides in the future.

Design of a new pH-activatable cell-penetrating peptide for drug delivery into tumor cells.

Cell-penetrating peptides (CPPs) have been considered as potential drug delivery vectors due to their remarkable membrane translocation capacity. However, lack of specificity and extreme systemic toxicity hamper their successful application for drug delivery. Here, we designed a new pH-activatable CPP, LHHLLHHLHHLLHH-NH2 (LH), by substitution of all lysines and two leucines of LKKLLKLLKKLLKL-NH2 (LK) with histidines. As expected, histidine-rich LH could be activated and penetrate into cells at pH 6.0, whereas its membrane transduction activity could be shielded at pH 7.4. In contrast, LK showed no obviously different cellular uptake at both pH conditions. Importantly, LH was significantly less cytotoxicity compared with LK at both pH values, suggesting a better safety for further application. In addition, after conjugation of camptothecin (CPT) with LH, this conjugate displayed remarkably pH-dependent antitumor activity than free CPT and LK-CPT. This study provides a new tumor pH-responsive CPP with low toxicity for selective anticancer drug delivery.