Heterochiral ß-Peptide Polymers Combating Multidrug-Resistant Cancers Effectively without Inducing Drug Resistance.

Multidrug resistance to chemotherapeutic drugs is one of the major causes for the failure of cancer treatment. Therefore, there is an urgent need to develop anticancer agents that can combat multidrug-resistant cancers effectively and mitigate drug resistance. Here, we report a rational design of anticancer heterochiral ß-peptide polymers as synthetic mimics of host defense peptides to combat multidrug-resistant cancers. The optimal polymer shows potent and broad-spectrum anticancer activities against multidrug-resistant cancer cells and is insusceptible to anticancer drug resistance owing to its membrane-damaging mechanism. The in vivo study indicates that the optimal polymer efficiently inhibits the growth and distant transfer of solid tumors and the metastasis and seeding of circulating tumor cells. Moreover, the polymer shows excellent biocompatibility during anticancer treatment on animals. In addition, the ß-peptide polymers address those prominent shortcomings of anticancer peptides and have superior stability against proteolysis, easy synthesis in large scale, and low cost. Collectively, the structural diversity and superior anticancer performance of ß-peptide polymers imply an effective strategy in designing and finding anticancer agents to combat multidrug-resistant cancers effectively while mitigating drug resistance.

Advance in Hybrid Peptides Synthesis.

Hybrid peptides with heterogeneous backbone are a class of peptide mimics with adjustable proteolytic stability obtained from incorporating unnatural amino acid residues into peptide backbone. α/ß-peptides and peptide/peptoid hybrids are two types of hybrid peptides that are widely studied for diverse applications, and several synthetic methods have been developed. In this mini review, the advance in hybrid peptide synthesis is summarized, including solution-phase method, solid-phase method, and novel polymerization method. Conventional solution-phase method and solid-phase method generally result in oligomers with defined sequences, while polymerization methods have advantages in preparing peptide hybrid polymers with high molecular weight with simple operation and low cost. In addition, the future development of polymerization method to realize the control of the peptide hybrid polymer sequence is discussed.

Protein corona investigations of polyplexes with varying hydrophobicity - From method development to in vitro studies.

In the field of non-viral drug delivery, polyplexes (PXs) represent an advanced investigated and highly promising tool for the delivery of nucleic acids. Upon encountering physiological fluids, they adsorb biological molecules to form a protein corona (PC), that influence PXs biodistribution, transfection efficiencies and targeting abilities. In an effort to understand protein - PX interactions and the effect of PX material on corona composition, we utilized cationic branched 10 kDa polyethyleneimine (b-PEI) and a hydrophobically modified nylon-3 polymer (NM0.2/CP0.8) within this study to develop appropriate methods for PC investigations. A centrifugation procedure for isolating hard corona - PX complexes (PCPXs) from soft corona proteins after incubating the PXs in fetal bovine serum (FBS) for PC formation was successfully optimized and the identification of proteins by a liquid chromatography-tandem mass spectrometry (LC-MS-MS) method clearly demonstrated that the PC composition is affected by the underlying PXs material. With regard to especially interesting functional proteins, which might be able to induce active targeting effects, several candidates could be detected on b-PEI and NM0.2/CP0.8 PXs. These results are of high interest to better understand how the design of PXs impacts the PC composition and subsequently PCPXs-cell interactions to enable precise adjustment of PXs for targeted drug delivery.

Host defense peptide mimicking cyclic peptoid polymers exerting strong activity against drug-resistant bacteria.

Extensive use of antibiotics accelerates the emergence of drug-resistant bacteria and related infections. Host defense peptides (HDPs) have been studied as promising and potential therapeutic candidates. However, their clinical applications of HDPs are limited due to their high cost of synthesis and low stability upon proteolysis. Therefore, HDP mimics have become a new approach to address the challenge of bacterial resistance. In this work, we design the amphiphilic peptoid polymers by mimicking the positively charged and hydrophobic structures of HDPs and synthesize a series of cyclic peptoid polymers efficiently via the polymerization on α-amino acid N-substituted glycine N-carboxyanhydrides (α-NNCAs) using 1,8-diazabicycloundec-7-ene (DBU) as the initiator. The optimal cyclic peptoid polymer, poly(Naeg0.7Npfbg0.3)20, displays strong antibacterial activities against drug-resistant bacteria, but low hemolysis and cytotoxicity. In addition, the mode-of-action study indicates that the antibacterial mechanism is associated with bacterial membrane interaction. Our study implies that HDP mimicking cyclic peptoid polymers have potential application in treating drug-resistant bacterial infections.

Microbial Metabolite Inspired ß-Peptide Polymers Displaying Potent and Selective Antifungal Activity.

Potent and selective antifungal agents are urgently needed due to the quick increase of serious invasive fungal infections and the limited antifungal drugs available. Microbial metabolites have been a rich source of antimicrobial agents and have inspired the authors to design and obtain potent and selective antifungal agents, poly(DL-diaminopropionic acid) (PDAP) from the ring-opening polymerization of ß-amino acid N-thiocarboxyanhydrides, by mimicking ε-poly-lysine. PDAP kills fungal cells by penetrating the fungal cytoplasm, generating reactive oxygen, and inducing fungal apoptosis. The optimal PDAP displays potent antifungal activity with minimum inhibitory concentration as low as 0.4 µg mL-1 against Candida albicans, negligible hemolysis and cytotoxicity, and no susceptibility to antifungal resistance. In addition, PDAP effectively inhibits the formation of fungal biofilms and eradicates the mature biofilms. In vivo studies show that PDAP is safe and effective in treating fungal keratitis, which suggests PDAPs as promising new antifungal agents.

Addressing MRSA infection and antibacterial resistance with peptoid polymers.

Methicillin-Resistant Staphylococcus aureus (MRSA) induced infection calls for antibacterial agents that are not prone to antimicrobial resistance. We prepare protease-resistant peptoid polymers with variable C-terminal functional groups using a ring-opening polymerization of N-substituted N-carboxyanhydrides (NNCA), which can provide peptoid polymers easily from the one-pot synthesis. We study the optimal polymer that displays effective activity against MRSA planktonic and persister cells, effective eradication of highly antibiotic-resistant MRSA biofilms, and potent anti-infectious performance in vivo using the wound infection model, the mouse keratitis model, and the mouse peritonitis model. Peptoid polymers show insusceptibility to antimicrobial resistance, which is a prominent merit of these antimicrobial agents. The low cost, convenient synthesis and structure diversity of peptoid polymers, the superior antimicrobial performance and therapeutic potential in treating MRSA infection altogether imply great potential of peptoid polymers as promising antibacterial agents in treating MRSA infection and alleviating antibiotic resistance.

Peptide polymer displaying potent activity against clinically isolated multidrug resistant Pseudomonas aeruginosa in vitro and in vivo.

Multidrug resistant (MDR) Pseudomonas aeruginosa has caused serious nosocomial infections owing to its high intrinsic resistance and ease of acquiring resistance to common antibiotics. There is an urgent need to develop antimicrobial agents against MDR Pseudomonas aeruginosa. Here we report a 27-mer peptide polymer 90 : 10 DLL : BLG, as a synthetic mimic of a host defense peptide, that displayed potent in vitro and in vivo activities against multiple strains of clinically isolated MDR Pseudomonas aeruginosa, performing even better than antibiotics within our study. This peptide polymer also showed negligible hemolysis and low cytotoxicity, as well as quick bacterial killing efficacy. The structural diversity of peptide polymers, their easy synthesis from lithium hexamethyldisilazide-initiated fast N-carboxyanhydride polymerization, and the excellent reproducibility of their chemical structure and biological profiles altogether suggested great potential for antimicrobial applications of peptide polymers as synthetic mimics of host defense peptides.

Host Defense Peptide Mimicking Peptide Polymer Exerting Fast, Broad Spectrum, and Potent Activities toward Clinically Isolated Multidrug-Resistant Bacteria.

Multidrug-resistant (MDR) bacteria have emerged quickly and have caused serious nosocomial infections. It is urgent to develop novel antimicrobial agents for treating MDR bacterial infections. In this study, we isolated 45 strains of bacteria from hospital patients and found shockingly that most of these strains were MDR to antimicrobial drugs. This inspired us to explore antimicrobial peptide polymers as synthetic mimics of host defense peptides in combating drug-resistant bacteria and the formidable antimicrobial challenge. We found that peptide polymer 80:20 DM:Bu (where DM is a hydrophilic/cationic subunit and Bu is a hydrophobic subunit) displayed fast bacterial killing, broad spectrum, and potent activity against clinically isolated strains of MDR bacteria. Moreover, peptide polymer 80:20 DM:Bu displayed potent in vivo antibacterial efficacy, comparable to the performance of polymyxin B, in a Pseudomonas aeruginosa (P. aeruginosa) infected rat full-thickness wound model. The peptide polymer can be easily synthesized from ring-opening polymerization with remarkable reproducibility in structural properties and biological activities. The peptide polymer's potent and broad spectrum antimicrobial activities against MDR bacteria in vitro and in vivo, resistance to proteolysis, and high structural diversity altogether imply a great potential of peptide polymer 80:20 DM:Bu in antimicrobial applications as synthetic mimics of host defense peptides.