Recent Advances in Peptides-Based Stimuli-Responsive Materials for Biomedical and Therapeutic Applications: A Review.

Smart materials are engineered materials that have one or more properties that are introduced in a controlled fashion by surrounding stimuli. Engineering of biomacromolecules like proteins into a smart material call for meticulous artistry. Peptides have grabbed notable attention as a preferred source for smart materials in the medicinal field, promoted by their versatile chemical and biophysical attributes of biocompatibility, and biodegradability. Recent advances in the synthesis of multifunctional peptides have proliferated their application in diverse domains: agriculture, nanotechnology, medicines, biosensors, therapeutics, and soft robotics. Stimuli such as pH, temperature, light, metal ions, and enzymes have vitalized physicochemical properties of peptides by augmented sensitivity, stability, and selectivity. This review elucidates recent (2018-2021) advances in the design and synthesis of smart materials, from stimuli-responsive peptides followed by their biomedical and therapeutic applications.

Modulation of prion polymerization and toxicity by rationally designed peptidomimetics.

Misfolding and aggregation of cellular prion protein is associated with a large array of neurological disorders commonly called the transmissible spongiform encephalopathies. Designing inhibitors against prions has remained a daunting task owing to limited information about mechanism(s) of their pathogenic self-assembly. Here, we explore the anti-prion properties of a combinatorial library of bispidine-based peptidomimetics (BPMs) that conjugate amino acids with hydrophobic and aromatic side chains. Keeping the bispidine unit unaltered, a series of structurally diverse BPMs were synthesized and tested for their prion-modulating properties. Administration of Leu- and Trp-BPMs delayed and completely inhibited the amyloidogenic conversion of human prion protein (HuPrP), respectively. We found that each BPM induced the HuPrP to form unique oligomeric nanostructures differing in their biophysical properties, cellular toxicities and response to conformation-specific antibodies. While Leu-BPMs were found to stabilize the oligomers, Trp-BPMs effected transient oligomerization, resulting in the formation of non-toxic, non-fibrillar aggregates. Yet another aromatic residue, Phe, however, accelerated the aggregation process in HuPrP. Molecular insights obtained through MD (molecular dynamics) simulations suggested that each BPM differently engages a conserved Tyr 169 residue at the α2-ß2 loop of HuPrP and affects the stability of α2 and α3 helices. Our results demonstrate that this new class of molecules having chemical scaffolds conjugating hydrophobic/aromatic residues could effectively modulate prion aggregation and toxicity.

Synthetic minimalistic tryptophan zippers as a chiroptical switch.

In this paper, we presented a new design strategy for a peptide-based chiral supramolecular assembly. A series of aryl linked peptides 1a-1f were designed and synthesized. The bis-urea peptides 1a-1c self-assembled into a helical supramolecular arrangement resembling Trp zipper (Trpzip) structures present in proteins. Interestingly, a dihydrogenphosphate anion, upon binding to the assembly, could invert the chirality of the supramolecular assembly which could be reverted to the original by the addition of water. This chiroptical behavior can be repeated several times. Microscopy analysis showed that the supramolecular helices were assembled to form spheres. In addition to that, we also found that the handedness of supramolecular chirality is dependent on the position of Trp residues on the aromatic scaffold. Both left and right handed helical supramolecular arrangements were obtained by placing l-Trp residues at different positions on the aromatic core. The unprecedented Trpzip in these designed small peptidomimetics will stimulate more work in the area of peptide-based assemblies.

Sortase-based bio-organic strategies for macromolecular synthesis.

Protein ligation sorted: SrtA is one of the molecules nature uses to perform chemoselective ligation on amazingly complex protein molecules. Sortase-mediated ligation (SML) with chemoselective reactions will find a variety of applications in chemistry, biology, and medicine in the near future.

Lysine-appended polydiacetylene scaffolds for human mesenchymal stem cells.

We report on the self-assembly based fabrication of fibrous polymers for tissue engineering applications. Directed self-assembly followed by polymerization of lysine-appended diacetylenes generated a variety of polymers (P1-P5) with distinct chemical properties. The self-assembly along with the conjugated double and triple bonds and rigid geometry of diacetylene backbone imposed a nanofibrous morphology on the resulting polymers. Chemical properties including wettability of the polymers were tuned by using lysine (Lys) with orthogonal protecting groups (Boc and Fmoc). These Lys-appended polydiacetylene scaffolds were compared in terms of their efficiency toward human mesenchymal stem cells adhesion and spreading. Interestingly, polymer P4 containing Lys N(α)-NH2 and Lys N(ε)-Boc with balanced wettability supported cell adhesion better than the more hydrophobic polymer P2 with N(ε)-Boc and N(α)-Fmoc or more hydrophilic polymer P5 containing free N(ε) and N(α) amino groups. The molecular level control in the fabrication of nanofibrous polymers compared with other existing methods for the generation of fibrous polymers is the hallmark of this work.

A Critical Review on the Identification of Pathogens by Employing Peptide-Based Electrochemical Biosensors.

In this era of emerging pathogenic diseases, prompt and accurate detection of pathogens is crucial. Disease diagnosis, environmental monitoring and food safety all rely heavily on the identification of pathogens. Peptide-based electrochemical sensors due to their rapid response times, specificity and sensitivity have emerged as promising tools in the identification of pathogens. This review emphasizes the importance of peptides in detection of pathogens and different peptide-based electrochemical biosensors for the detection of pathogens. Peptides offer several advantages including strong binding affinity to a diverse array of pathogens including bacteria, viruses and fungi, tunable specificity and simple synthesis. Peptide-based electrochemical sensors employ different electrochemical techniques such as differential pulse voltammetry (DPV), cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), amperometry and linear sweep voltammetry (LSV). The efficacy of peptide-based biosensors in detecting low concentrations of pathogens is highlighted, demonstrating the promising applications of these biosensors in early diagnosis and real-time monitoring. In addition, the review also addresses the current challenges in the field such as peptide stability, sensor reproducibility and interference from complex biological matrices. This review suggests potential resolutions and avenues for progress such as the development of multiplexed detection systems that can concurrently identify multiple pathogens and developments in peptide design and sensor miniaturization. In summary, this review highlights the substantial advancements and potential possibilities of peptide-based electrochemical biosensors in the realm of pathogen detection, thereby facilitating the development of safer and more effective diagnostic tools.

Correction: Bispidine-Amino Acid Conjugates Act as a Novel Scaffold for the Design of Antivirals That Block Japanese Encephalitis Virus Replication.

[This corrects the article DOI: 10.1371/journal.pntd.0002005.].

Recent Advances in Bioactive Peptides as Functional Food for Health Promotions and Medicinal Applications.

Bioactive peptides obtained from natural resources are useful due to their ability to prevent the risk of dreadful conditions such as hypertension, cancers, obesity and cardiovascular diseases. Proteins from food, plants, animals and dairy products are chemically or enzymatically hydrolyzed or fermented in the presence of microbes to produce bioactive peptides. Bioactive peptides are antioxidant, antihypertensive, anti-inflammatory, antiproliferative, antibacterial, anticancer, antimicrobial and some of them also show multiple bioactivities. Also, bioactive peptides offer much potential as nutraceuticals or functional food components. This paper reviews recent progress (2020-2022) on bioactive peptides derived from food, animals, plants, and dairy products. Emphasis is given to their production, purification, and potential use for health promotions and medicinal applications.

Ligand-protected nanoclusters and their role in agriculture, sensing and allied applications.

Nano biotechnology, when coupled with green chemistry, can revolutionize human life because of the vast opportunities and benefits it can offer to the quality of human life. Luminescent metal nanoclusters (NCs) have recently developed as a potential research area with applications in different areas like medical, imaging, sensing etc. Recently these new candidates have proved to be beneficial in the food supply chain enabling controlled release of nutrients, pesticides and as nanosensors for the detection of contaminants and play roles in healthy food storage and maintaining food quality. An assortment of nanomaterials has been employed for these applications and reviews have been published on the use of nanotechnology in agriculture. Ligand-protected metal nanoclusters are a distinctive class of small organic-inorganic nanostructures that garnered immense research interest in recent years owing to their stability at specific "magic size" compositions along with tunable properties that make them promising candidates for a wide range of nanotechnology-based applications. This review tries to consolidate the recent developments in the area of ligand-protected nanoclusters in connection with the detection of pesticides, food contaminants, heavy metal ions and plant growth monitoring for healthy agricultural practices. Its antimicrobial activity to manage the microbial contamination is highlighted. The review also throws light on the various perspectives by which food production and allied areas will be transformed in future.

Novel peptidylated surfaces for interference-free electrochemical detection of cardiac troponin I.

Novel peptidylated surfaces were designed to minimise interferences when electrochemically detecting cardiac troponin I in complex biological samples. Disulfide-cored peptide dendrons featuring carbomethoxy groups were self-assembled on gold electrodes. The carbomethoxy groups were deprotected to obtain carboxylic groups used to immobilise antibodies for cardiac troponin I marker. The chemisorption of two types of peptides, one containing triazole and the other with native peptide bonds, on a gold substrate was studied by quartz crystal microbalance (QCM), surface plasmon resonance (SPR) and X-ray photoelectron spectroscopy (XPS). Peptides formed ordered self-assembled monolayers, contributing to a more efficient display of the subsequently immobilised antibodies towards their binding to the antigen. As a result, electrochemical immunosensors prepared by self-assembly of peptides afforded higher sensitivities for cardiac troponin I than those prepared by the chemisorption of alkane thiolated compounds. Triazolic peptide-modified immunosensors showed extraordinary sensitivity towards cardiac troponin I [1.7µA/(ng/mL) in phosphate buffer], but suffered from surface fouling in 10% serum. Modification with non-triazolic peptides gave rise to anti-fouling properties and still enabled the detection of cardiac troponin I at pg/mL concentrations in 10% serum without significant matrix effects.

Bispidine as a helix inducing scaffold: examples of helically folded linear peptides.

We designed and synthesized bispidine-anchored peptides and showed that these peptides as small as (containing four chiral α-amino acid residues) adopt a right handed helical conformation. Bispidine anchored linear peptide adopts a helical conformation in solution and in the solid state.

Bispidine-amino acid conjugates act as a novel scaffold for the design of antivirals that block Japanese encephalitis virus replication.

BACKGROUND: Japanese encephalitis virus (JEV) is a major cause of viral encephalitis in South and South-East Asia. Lack of antivirals and non-availability of affordable vaccines in these endemic areas are a major setback in combating JEV and other closely related viruses such as West Nile virus and dengue virus. Protein secondary structure mimetics are excellent candidates for inhibiting the protein-protein interactions and therefore serve as an attractive tool in drug development. We synthesized derivatives containing the backbone of naturally occurring lupin alkaloid, sparteine, which act as protein secondary structure mimetics and show that these compounds exhibit antiviral properties. METHODOLOGY/PRINCIPAL FINDINGS: In this study we have identified 3,7-diazabicyclo[3.3.1]nonane, commonly called bispidine, as a privileged scaffold to synthesize effective antiviral agents. We have synthesized derivatives of bispidine conjugated with amino acids and found that hydrophobic amino acid residues showed antiviral properties against JEV. We identified a tryptophan derivative, Bisp-W, which at 5 µM concentration inhibited JEV infection in neuroblastoma cells by more than 100-fold. Viral inhibition was at a stage post-entry and prior to viral protein translation possibly at viral RNA replication. We show that similar concentration of Bisp-W was capable of inhibiting viral infection of two other encephalitic viruses namely, West Nile virus and Chandipura virus. CONCLUSIONS/SIGNIFICANCE: We have demonstrated that the amino-acid conjugates of 3,7-diazabicyclo[3.3.1]nonane can serve as a molecular scaffold for development of potent antivirals against encephalitic viruses. Our findings will provide a novel platform to develop effective inhibitors of JEV and perhaps other RNA viruses causing encephalitis.