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.

Impact of Antifouling PEG Layer on the Performance of Functional Peptides in Regulating Cell Behaviors.

Cell adhesive and other functional peptides (such as RGD, KRSR, YIGSR, VAPG, and BMP-2 peptides) are extensively studied and utilized in tissue engineering scaffolds and biomedical devices to modulate cell functions. Though PEG is frequently used as the antifouling layer, it is unclear how it affects the performance of functional peptides. By analyzing the impact of PEG at short (OEG4), medium (OEG8), and long chain length (PEG2K), we reveal that PEG chain length is critical and a medium-length PEG enables functional peptides to display their optimal and genuine functions in cell adhesion, migration, and differentiation by providing excellent antifouling to minimize background noise of unwanted cell adhesion and high enough surface density of functional peptides. Our result provides new avenues for maximizing the genuine functions of peptides. This study also provides a solution to prevent the heterogeneous and even divergent results caused by inappropriate choice of antifouling PEG and provides a general guidance in identifying new functional peptides.

AI-guided few-shot inverse design of HDP-mimicking polymers against drug-resistant bacteria.

Host defense peptide (HDP)-mimicking polymers are promising therapeutic alternatives to antibiotics and have large-scale untapped potential. Artificial intelligence (AI) exhibits promising performance on large-scale chemical-content design, however, existing AI methods face difficulties on scarcity data in each family of HDP-mimicking polymers (<102), much smaller than public polymer datasets (>105), and multi-constraints on properties and structures when exploring high-dimensional polymer space. Herein, we develop a universal AI-guided few-shot inverse design framework by designing multi-modal representations to enrich polymer information for predictions and creating a graph grammar distillation for chemical space restriction to improve the efficiency of multi-constrained polymer generation with reinforcement learning. Exampled with HDP-mimicking ß-amino acid polymers, we successfully simulate predictions of over 105 polymers and identify 83 optimal polymers. Furthermore, we synthesize an optimal polymer DM0.8iPen0.2 and find that this polymer exhibits broad-spectrum and potent antibacterial activity against multiple clinically isolated antibiotic-resistant pathogens, validating the effectiveness of AI-guided design strategy.

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.

Dual mechanism ß-amino acid polymers promoting cell adhesion.

Cell adhesion has tremendous impact on the function of culture platforms and implants. Cell-adhesive proteins and peptides have been extensively used for decades to promote cell adhesion, however, their application suffers from their easy enzymatic degradation, difficulty in large-scale preparation and expensiveness. To develop the next-generation cell-adhesive materials, we mimic the cell adhesion functions and mechanisms of RGD and KRSR peptides and design cell-adhesive cationic-hydrophobic amphiphilic ß-amino acid polymers that are stable upon proteolysis and easily prepared in large scale at low cost. The optimal polymer strongly promotes cell adhesion, using preosteoblast cell as a model, by following dual mechanisms that are independent of sequence and chirality of the statistic copolymer. Our strategy opens avenues in designing the next-generation cell-adhesive materials and may guide future studies and applications.

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.

A sandcastle worm-inspired strategy to functionalize wet hydrogels.

Hydrogels have been extensively used in many fields. Current synthesis of functional hydrogels requires incorporation of functional molecules either before or during gelation via the pre-organized reactive site along the polymer chains within hydrogels, which is tedious for polymer synthesis and not flexible for different types of hydrogels. Inspired by sandcastle worm, we develop a simple one-step strategy to functionalize wet hydrogels using molecules bearing an adhesive dibutylamine-DOPA-lysine-DOPA tripeptide. This tripeptide can be easily modified with various functional groups to initiate diverse types of polymerizations and provide functional polymers with a terminal adhesive tripeptide. Such functional molecules enable direct modification of wet hydrogels to acquire biological functions such as antimicrobial, cell adhesion and wound repair. The strategy has a tunable functionalization degree and a stable attachment of functional molecules, which provides a tool for direct and convenient modification of wet hydrogels to provide them with diverse functions and applications.