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ACS Nano May 2023Vitiligo, a common skin disease that seriously affects 0.5-2.0% of the worldwide population, lacks approved therapeutics due to a wide range of adverse side effects. As...
Vitiligo, a common skin disease that seriously affects 0.5-2.0% of the worldwide population, lacks approved therapeutics due to a wide range of adverse side effects. As a key regulator of skin pigmentation, MC1R may be an effective therapeutic target for vitiligo. Herein, we report an MC1R peptide agonist that directly self-assembles into nanofibrils that form a hydrogel matrix under normal physiological conditions. This hydrogel exhibits higher stability than free peptides, sustained release, rapid recovery from shear-thinning, and resistance to enzymatic proteolysis. Furthermore, this peptidal MC1R agonist upregulates tyrosinase, tyrosinase-related protein-1 (TYRP-1), and tyrosinase-related protein-2 (TYRP-2) to stimulate melanin synthesis. More importantly, MC1R agonist hydrogel promotes skin pigmentation in mice more potently than free MC1R agonist. This study supports the development of this MC1R agonist hydrogel as a promising pharmacological intervention for vitiligo.
Topics: Animals; Mice; Skin Pigmentation; Vitiligo; Hydrogels; Receptor, Melanocortin, Type 1; Peptides; Pigmentation
PubMed: 37115703
DOI: 10.1021/acsnano.3c01960 -
Accounts of Chemical Research Mar 2016The development of sequence-specific peptidomimetics has led to a variety of fascinating discoveries in chemical biology. Many peptidomimetics can mimic primary,...
The development of sequence-specific peptidomimetics has led to a variety of fascinating discoveries in chemical biology. Many peptidomimetics can mimic primary, secondary, and even tertiary structure of peptides and proteins, and because of their unnatural backbones, they also possess significantly enhanced resistance to enzymatic hydrolysis, improved bioavailability, and chemodiversity. It is known that peptide nucleic acids (PNAs) are peptidic sequences developed for the mimicry of nucleic acids; however, their unique backbone as the molecular scaffold of peptidomimetics to mimic structure and function of bioactive peptides has not been investigated systematically. As such, we recently developed a new class of peptidomimetics, "γ-AApeptides", based on the chiral γ-PNA backbone. They are termed γ-AApeptides because they are the oligomers of γ-substituted-N-acylated-N-aminoethyl amino acids. Similar to other classes of peptidomimetics, γ-AApeptides are also resistant to proteolytic degradation and possess the potential to enhance chemodiversity. Moreover, in our scientific journey on the exploration of this class of peptidomimetics, we have discovered some intriguing structures and functions of γ-AApeptides. In this Account, we summarize the current development and application of γ-AApeptides with biological potential. Briefly, both linear and cyclic (either through head-to-tail or head-to-side-chain cyclization) γ-AApeptides with diverse functional groups can be synthesized easily on the solid phase using the synthetic protocol we developed. γ-AApeptides could mimic the primary structure of peptides, as they project the same number of side chains as peptides of the same lengths. For instance, they could mimic the Tat peptide to permeate cell membranes and bind to HIV RNA with high specificity and affinity. Certain γ-AApeptides show similar activity to the RGD peptide and target integrin specifically on the cell surface. γ-AApeptides with function akin to fMLF peptides are also identified. More importantly, we found that γ-AApeptides can fold into discrete secondary structures, such as helical and β-turn-like structures. Therefore, they could be rationally designed for a range of biological applications. For instance, γ-AApeptides can mimic host-defense peptides and display potent and broad-spectrum activity toward a panel of drug-resistant bacterial pathogens. Meanwhile, because of their stability against proteolysis and their chemodiversity, γ-AApeptides are also amenable for combinatorial screening. We demonstrate that, through combinatorial selection, certain γ-AApeptides are identified to inhibit Aβ40 peptide aggregation, suggesting their potential use as a molecular probe to intervene in Alzheimer's disease. In addition, a few γ-AApeptides identified from the γ-AApeptide library have been shown to bind to the DNA-binding domain of STAT3 and antagonize STAT3/DNA interactions. Our studies suggest that, with further studies and exploration on both structures and functions, γ-AApeptides may emerge to be a new class of peptidomimetics that play an important role in chemical biology and biomedical sciences.
Topics: Microscopy, Electron, Transmission; Peptides; Protein Conformation
PubMed: 26900964
DOI: 10.1021/acs.accounts.5b00492 -
Accounts of Chemical Research Jul 2015Natural products of peptidic origin often represent a rich source of medically relevant compounds. The synthesis of such polypeptides in nature is either initiated by... (Review)
Review
Natural products of peptidic origin often represent a rich source of medically relevant compounds. The synthesis of such polypeptides in nature is either initiated by deciphering the genetic code on the ribosome during the translation process or driven by ribosome-independent processes. In the latter case, highly modified bioactive peptides are assembled by multimodular enzymes designated as nonribosomal peptide synthetases (NRPS) that act as a protein-template to generate chemically diverse peptides. On the other hand, the ribosome-dependent strategy, although relying strictly on the 20-22 proteinogenic amino acids, generates structural diversity by extensive post-translational-modification. This strategy seems to be highly distributed in all kingdoms of life. One example for this is the lasso peptides, which are an emerging class of ribosomally assembled and post-translationally modified peptides (RiPPs) from bacteria that were first described in 1991. A wide range of interesting biological activities are known for these compounds, including antimicrobial, enzyme inhibitory, and receptor antagonistic activities. Since 2008, genome mining approaches allowed the targeted isolation and characterization of such molecules and helped to better understand this compound class and their biosynthesis. Their defining structural feature is a macrolactam ring that is threaded by the C-terminal tail and held in position by sterically demanding residues above and below the ring, resulting in a unique topology that is reminiscent of a lariat knot. The ring closure is achieved by an isopeptide bond formed between the N-terminal α-amino group of a glycine, alanine, serine, or cysteine and the carboxylic acid side chain of an aspartate or glutamate, which can be located at positions 7, 8, or 9 of the amino acid sequence. In this Account, we discuss the newest findings about these compounds, their biosynthesis, and their physicochemical properties. This includes the suggested mechanism through which the precursor peptide is enzymatically processed into a mature lasso peptide and crucial residues for enzymatic recognition. Furthermore, we highlight new insights considering the protease and thermal stability of lasso peptides and discuss why seven amino acid residue rings are likely to be the lower limit feasible for this compound class. To elucidate their fascinating three-dimensional structures, NMR spectroscopy is commonly employed. Therefore, the general methodology to elucidate these structures by NMR will be discussed and pitfalls for these approaches are highlighted. In addition, new tools provided by recent investigations to assess and prove the lasso topology without a complete structure elucidation will be summarized. These include techniques like ion mobility-mass spectrometry and a combined approach of thermal and carboxypeptidase treatment with subsequent LC-MS analysis. Nevertheless, even though much was learned about these compounds in recent years, their true native function and the exact enzymatic mechanism of their maturation remain elusive.
Topics: Bacteria; Biological Products; Models, Molecular; Peptides
PubMed: 26079760
DOI: 10.1021/acs.accounts.5b00156 -
Life Sciences Jan 2021Humanin (HN) is a small mitochondrial-derived cytoprotective polypeptide encoded by mtDNA. HN exhibits protective effects in several cell types, including leukocytes,... (Review)
Review
Humanin (HN) is a small mitochondrial-derived cytoprotective polypeptide encoded by mtDNA. HN exhibits protective effects in several cell types, including leukocytes, germ cells, neurons, tissues against cellular stress conditions and apoptosis through regulating various signaling mechanisms, such as JAK/STAT pathway and interaction of BCL-2 family of protein. HN is an essential cytoprotective peptide in the human body that regulates mitochondrial functions under stress conditions. The present review aims to evaluate HN peptide's antiapoptotic activities as a potential therapeutic target in the treatment of cancer, diabetes mellitus, male infertility, bone-related diseases, cardiac diseases, and brain diseases. Based on in vitro and in vivo studies, HN significantly suppressed the apoptosis during the treatment of bone osteoporosis, cardiovascular diseases, diabetes mellitus, and neurodegenerative diseases. According to accumulated data, it is concluded that HN exerts the proapoptotic activity of TNF-α in cancer, which makes HN as a novel therapeutic agent in the treatment of cancer and suggested that along with HN, the development of another mitochondrial-derived peptide could be a viable therapeutic option against different oxidative stress and apoptosis-related diseases.
Topics: Amino Acid Sequence; Animals; Apoptosis; Apoptosis Regulatory Proteins; Cytoprotection; Diabetes Mellitus; Humans; Intracellular Signaling Peptides and Proteins; Mitochondria; Neoplasms; Neurodegenerative Diseases
PubMed: 33130077
DOI: 10.1016/j.lfs.2020.118679 -
Journal of Chemical Information and... Jul 2023Most processes at the water-membrane interface often involve protonation events in proteins or peptides that trigger important biological functions and events. This is...
Most processes at the water-membrane interface often involve protonation events in proteins or peptides that trigger important biological functions and events. This is the working principle behind the pHLIP peptide technology. A key titrating aspartate (Asp14 in ) is required to protonate to induce the insertion process, increase its thermodynamic stability when membrane-embedded, and trigger the peptide's overall clinical functionality. At the core of pHLIP properties, the aspartate p and protonation are a consequence of the residue side chain sensing the changing surrounding environment. In this work, we characterized how the microenvironment of the key aspartate residue (Asp13 in the investigated pHLIP variants) can be modulated by a simple point mutation of a cationic residue (ArgX) at distinct sequence positions (R10, R14, R15, and R17). We carried out a multidisciplinary study using pHRE simulations and experimental measurements. Fluorescence and circular dichroism measurements were carried out to establish the stability of pHLIP variants in state III and establish the kinetics of the insertion and exit of the peptide from the membrane. We estimated the contribution of the arginine to the local electrostatic microenvironment, which promotes or hinders other electrostatic players from coexisting in the Asp interaction shell. Our data indicate that the stability and kinetics of the peptide insertion and exit from the membrane are altered when Arg is topologically available for a direct salt-bridge formation with Asp13. Hence, the position of arginine contributes to fine-tuning the pH responses of pHLIP peptides, which finds wide applications in clinics.
Topics: Lipid Bilayers; Aspartic Acid; Membrane Proteins; Peptides; Hydrogen-Ion Concentration
PubMed: 37395685
DOI: 10.1021/acs.jcim.3c00360 -
Methods in Molecular Biology (Clifton,... 2020The application of designer peptides in medicinal chemistry, chemical biology, and materials science has generated new interest in synthetic methods for the structural...
The application of designer peptides in medicinal chemistry, chemical biology, and materials science has generated new interest in synthetic methods for the structural modification of amino acids. Strategies which facilitate the direct diversification of proteinogenic functional groups within unprotected peptide substrates are particularly attractive as they leverage modern solution- and solid-phase protocols-tools which are now both robust and routine-for the synthesis of native peptides. Accordingly, a recent approach to the decarboxylative functionalization of peptidic carboxylic acids, including aspartic/glutamic acid residues and α-carboxylic acids, has proven to be a promising new strategy for peptide modification. This synthetic method merges conventional strategies for the activation of carboxylic acids with transition metal-catalyzed cross-coupling chemistry to forge new C-C bonds for the late-stage introduction of valuable synthetic handles. This chapter details a step-by-step protocol for the activation and nickel-catalyzed decarboxylative alkylation of a simple peptide substrate to highlight the broad utility of this strategy for the synthesis of designer peptides.
Topics: Amino Acids; Carboxylic Acids; Decarboxylation; Ligands; Metals; Nickel; Oxidative Coupling; Peptides; Solid-Phase Synthesis Techniques
PubMed: 31879933
DOI: 10.1007/978-1-0716-0227-0_19 -
Neurochemical Research Sep 2022Ischemic stroke leads to acute neuron death and forms an injured core, triggering delayed cell death at the penumbra. The impaired brain functions after ischemic stroke... (Review)
Review
Ischemic stroke leads to acute neuron death and forms an injured core, triggering delayed cell death at the penumbra. The impaired brain functions after ischemic stroke are hardly recovered because of the limited regenerative properties. However, recent rodent intervention studies manipulating the extracellular environments at the subacute phase shed new light on the regenerative potency of the injured brain. This review introduces the rational design of artificial extracellular matrix (ECM) mimics using supramolecular peptidic scaffolds, which self-assemble via non-covalent bonds and form hydrogels. The facile customizability of the peptide structures allows tuning the hydrogels' physical and biochemical properties, such as charge states, hydrophobicity, cell adhesiveness, stiffness, and stimuli responses. Supramolecular peptidic materials can create safer and more economical drugs than polymer materials and cell transplantation. We also discuss the importance of activating developmental programs for the recovery at the subacute phase of ischemic stroke. Self-assembling molecular medicine mimicking the ECMs and activating developmental programs may stand as a new drug modality of regenerative medicine in various tissues.
Topics: Extracellular Matrix; Humans; Hydrogels; Ischemic Stroke; Molecular Medicine; Peptides; Regenerative Medicine; Tissue Engineering
PubMed: 35666393
DOI: 10.1007/s11064-022-03638-5 -
Advances in Experimental Medicine and... 2016Peptides with the cystine-knot architecture, often termed knottins, are promising scaffolds for biomolecular engineering. These unique molecules combine diverse... (Review)
Review
Peptides with the cystine-knot architecture, often termed knottins, are promising scaffolds for biomolecular engineering. These unique molecules combine diverse bioactivities with excellent structural, thermal, and proteolytical stability. Being different in the composition and structure of their amino acid backbone, knottins share the same core element, namely cystine knot, which is built by six cysteine residues forming three disulfides upon oxidative folding. This motif ensures a notably rigid framework that highly tolerates both rational and combinatorial changes in the primary structure. Being accessible through recombinant production and total chemical synthesis, cystine-knot miniproteins can be endowed with novel bioactivities by variation of surface-exposed loops and incorporation of non-natural elements within their non-conserved regions towards the generation of tailor-made peptidic compounds. In this chapter the topology of cystine-knot peptides, their synthesis and applications for diagnostics and therapy is discussed.
Topics: Animals; Cystine-Knot Miniproteins; Drug Design; Humans; Neoplasms; Peptide Fragments; Protein Engineering
PubMed: 27236555
DOI: 10.1007/978-3-319-32805-8_7 -
Peptides May 2015Peptides are versatile and attractive biomolecules that can be applied to modulate genetic mechanisms like alternative splicing. In this process, a single transcript... (Review)
Review
Peptides are versatile and attractive biomolecules that can be applied to modulate genetic mechanisms like alternative splicing. In this process, a single transcript yields different mature RNAs leading to the production of protein isoforms with diverse or even antagonistic functions. During splicing events, errors can be caused either by mutations present in the genome or by defects or imbalances in regulatory protein factors. In any case, defects in alternative splicing have been related to several genetic diseases including muscular dystrophy, Alzheimer's disease and cancer from almost every origin. One of the most effective approaches to redirect alternative splicing events has been to attach cell-penetrating peptides to oligonucleotides that can modulate a single splicing event and restore correct gene expression. Here, we summarize how natural existing and bioengineered peptides have been applied over the last few years to regulate alternative splicing and genetic expression. Under different genetic and cellular backgrounds, peptides have been shown to function as potent vehicles for splice correction, and their therapeutic benefits have reached clinical trials and patenting stages, emphasizing the use of regulatory peptides as an exciting therapeutic tool for the treatment of different genetic diseases.
Topics: Alternative Splicing; Amino Acid Sequence; Animals; Base Sequence; Cell-Penetrating Peptides; Genetic Diseases, Inborn; Humans; Molecular Sequence Data; Peptide Nucleic Acids; Protein Isoforms; Transfection
PubMed: 25748022
DOI: 10.1016/j.peptides.2015.02.006 -
International Journal of Pharmaceutics Jul 2021The physical and chemical stability of therapeutic peptides presents challenges in developing robust formulations. The stability of the formulation affects product...
The physical and chemical stability of therapeutic peptides presents challenges in developing robust formulations. The stability of the formulation affects product safety, efficacy and quality. Therefore, an understanding of the effects of formulation variables on the peptide's conformational structure and on its possible physical and chemical degradation is vital. To this end, computational and experimental analysis were employed to investigate the impact of formulation, peptide folding and product handling on oxidation, fibrillar aggregation and gelation of teriparatide. Teriparatide was used as a model drug due to the correlation of its conformation in solution with its pharmacological activity. Fibrillar aggregation and gelation were monitored using four orthogonal techniques. An innovative, automated platform coupled with ion mobility mass spectrometry was used for profiling chemical degradants. Increases in teriparatide concentration, pH, and ionic strength were found to increase the rate of fibrillar aggregation and gelation. Conversely, an increase in peptide folding and stabilization of the folded structures was found to decrease the rate of fibrillar aggregation and gelation. Moreover, the rate of oxidation was found to be inversely related to its solution concentration and extent of peptide folding. The present study provides an insight into formulation strategies designed to reduce the potential risk of physical and chemical degradation of peptides with a defined conformation.
Topics: Molecular Conformation; Osmolar Concentration; Oxidation-Reduction; Peptides
PubMed: 33961953
DOI: 10.1016/j.ijpharm.2021.120677