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Chimia Jun 2021The new Energypolis campus brings together the skills of EPFL Valais-Wallis, HES-SO Valais-Wallis, and the Ark Foundation's services. Together these partners respond to... (Review)
Review
The new Energypolis campus brings together the skills of EPFL Valais-Wallis, HES-SO Valais-Wallis, and the Ark Foundation's services. Together these partners respond to today's major concerns in the domains of energy, health, and the environment cutting-edge technology. The spirit of this new campus is to foster innovation in these disciplines and emulate the creation of start-up companies. The HES-SO hosts the School of Engineering (HEI) at this campus, which includes the following degree programmes: Life Technologies, Systems Engineering and Energy and Environmental Engineering, as well as their corresponding applied research institutes. Peptide technologies belong to the many activities that are carrying out in the Institute of Life Technologies. The present review summarizes the peptide technologies that are currently under development, that is, the regioselective labeling of therapeutic antibodies for cancer imaging, the development of peptide antivirals and antimicrobials for the treatment of infectious diseases, targeting of drugs conjugated to peptidic scaffolds as well as engineering of biomaterials.
Topics: Anti-Infective Agents; Peptides; Technology
PubMed: 34233821
DOI: 10.2533/chimia.2021.539 -
Acta Biomaterialia Oct 2021Currently approved replication-competent and inactivated vaccines are limited by excessive reactogenicity and poor safety profiles, while subunit vaccines are often... (Review)
Review
Currently approved replication-competent and inactivated vaccines are limited by excessive reactogenicity and poor safety profiles, while subunit vaccines are often insufficiently immunogenic without co-administering exogenous adjuvants. Self-assembling peptide-, peptidomimetic-, and protein-based biomaterials offer a means to overcome these challenges through their inherent modularity, multivalency, and biocompatibility. As these scaffolds are biologically derived and present antigenic arrays reminiscent of natural viruses, they are prone to immune recognition and are uniquely capable of functioning as self-adjuvanting vaccine delivery vehicles that improve humoral and cellular responses. Beyond this intrinsic immunological advantage, the wide range of available amino acids allows for facile de novo design or straightforward modifications to existing sequences. This has permitted the development of vaccines and immunotherapies tailored to specific disease models, as well as generalizable platforms that have been successfully applied to prevent or treat numerous infectious and non-infectious diseases. In this review, we briefly introduce the immune system, discuss the structural determinants of coiled coils, β-sheets, peptide amphiphiles, and protein subunit nanoparticles, and highlight the utility of these materials using notable examples of their innate and adaptive immunomodulatory capacity. STATEMENT OF SIGNIFICANCE: Subunit vaccines have recently gained considerable attention due to their favorable safety profiles relative to traditional whole-cell vaccines; however, their reduced efficacy requires co-administration of reactogenic adjuvants to boost immune responses. This has led to collaborative efforts between engineers and immunologists to develop nanomaterial-based vaccination platforms that can elicit protection without deleterious side effects. Self-assembling peptidic biomaterials are a particularly attractive approach to this problem, as their structure and function can be controlled through primary sequence design and their capacity for multivalent presentation of antigens grants them intrinsic self-adjuvanticity. This review introduces the various architectures adopted by self-assembling peptides and discusses their application as modulators of innate and adaptive immunity.
Topics: Adaptive Immunity; Adjuvants, Immunologic; Antigens; Peptides; Vaccines, Subunit
PubMed: 34010691
DOI: 10.1016/j.actbio.2021.05.003 -
Molecules (Basel, Switzerland) Feb 2020To penetrate solid tumors, low molecular weight (Mw < 10 KDa) compounds have an edge over antibodies: their higher penetration because of their small size. Because of... (Review)
Review
To penetrate solid tumors, low molecular weight (Mw < 10 KDa) compounds have an edge over antibodies: their higher penetration because of their small size. Because of the dense stroma and high interstitial fluid pressure of solid tumors, the penetration of higher Mw compounds is unfavored and being small thus becomes an advantage. This review covers a wide range of peptidic ligands-linear, cyclic, macrocyclic and cyclotidic peptides-to target tumors: We describe the main tools to identify peptides experimentally, such as phage display, and the possible chemical modifications to enhance the properties of the identified peptides. We also review in silico identification of peptides and the most salient non-peptidic ligands in clinical stages. We later focus the attention on the current validated ligands available to target different tumor compartments: blood vessels, extracelullar matrix, and tumor associated macrophages. The clinical advances and failures of these ligands and their therapeutic conjugates will be discussed. We aim to present the reader with the state-of-the-art in targeting tumors, by using low Mw molecules, and the tools to identify new ligands.
Topics: Animals; Cell Surface Display Techniques; Extracellular Matrix; Humans; Macrophages; Neoplasms; Peptides
PubMed: 32069856
DOI: 10.3390/molecules25040808 -
Accounts of Chemical Research May 2022Biologically active peptides are a major growing class of drugs, but their therapeutic potential is constrained by several limitations including bioavailability and poor... (Review)
Review
Biologically active peptides are a major growing class of drugs, but their therapeutic potential is constrained by several limitations including bioavailability and poor pharmacokinetics. The attachment of functional groups like lipids has proven to be a robust and effective strategy for improving their therapeutic potential. Biochemical and bioactivity-guided screening efforts have identified the cyanobactins as a large class of ribosomally synthesized and post-translationally modified peptides (RiPPs) that are modified with lipids. These lipids are attached by the F superfamily of peptide prenyltransferase enzymes that utilize 5-carbon (prenylation) or 10-carbon (geranylation) donors. The chemical structures of various cyanobactins initially showed isoprenoid attachments on Ser, Thr, or Tyr. Biochemical characterization of the F prenyltransferases from the corresponding clusters shows that the different enzymes have different acceptor residue specificities but are otherwise remarkably sequence tolerant. Hence, these enzymes are well suited for biotechnological applications. The crystal structure of the Tyr -prenyltransferase PagF reveals that the F enzyme shares a domain architecture reminiscent of a canonical ABBA prenyltransferase fold but lacks secondary structural elements necessary to form an enclosed active site. Binding of either cyclic or linear peptides is sufficient to close the active site to allow for productive catalysis, explaining why these enzymes cannot use isolated amino acids as substrates.Almost all characterized isoprenylated cyanobactins are modified with 5-carbon isoprenoids. However, chemical characterization demonstrates that the piricyclamides are modified with a 10-carbon geranyl moiety, and in vitro reconstitution of the corresponding PirF shows that the enzyme is a geranyltransferase. Structural analysis of PirF shows an active site nearly identical with that of the PagF prenyltransferase but with a single amino acid substitution. Of note, mutation at this residue in PagF or PirF can completely switch the isoprenoid donor specificity of these enzymes. Recent efforts have resulted in significant expansion of the F family with enzymes identified that can carry out -prenylations of Trp, -prenylations of Trp, and bis--prenylations of Arg. Additional genome-guided efforts based on the sequence of F enzymes identify linear cyanobactins that are α--prenylated and α--methylated by a bifunctional prenyltransferase/methyltransferase fusion and a bis-α-- and α--prenylated linear peptide. The discovery of these different classes of prenyltransferases with diverse acceptor residue specificities expands the biosynthetic toolkit for enzymatic prenylation of peptide substrates.In this Account, we review the current knowledge scope of the F family of peptide prenyltransferases, focusing on the biochemical, structure-function, and chemical characterization studies that have been carried out in our laboratories. These enzymes are easily amenable for diversity-oriented synthetic efforts as they can accommodate substrate peptides of diverse sequences and are thus attractive catalysts for use in synthetic biology approaches to generate high-value peptidic therapeutics.
Topics: Carbon; Catalysis; Dimethylallyltranstransferase; Lipids; Peptides; Terpenes
PubMed: 35442036
DOI: 10.1021/acs.accounts.2c00108 -
Scientific Reports Nov 2021Palustrin-Ca (GFLDIIKDTGKEFAVKILNNLKCKLAGGCPP) is a host defence peptide with potent antimicrobial and anticancer activities, first isolated from the skin of the...
Palustrin-Ca (GFLDIIKDTGKEFAVKILNNLKCKLAGGCPP) is a host defence peptide with potent antimicrobial and anticancer activities, first isolated from the skin of the American bullfrog Lithobates catesbeianus. The peptide is 31 amino acid residues long, cationic and amphipathic. Two-dimensional NMR spectroscopy was employed to characterise its three-dimensional structure in a 50/50% water/2,2,2-trifluoroethanol-[Formula: see text] mixture. The structure is defined by an [Formula: see text]-helix that spans between Ile[Formula: see text]-Ala[Formula: see text], and a cyclic disulfide-bridged domain at the C-terminal end of the peptide sequence, between residues 23 and 29. A molecular dynamics simulation was employed to model the peptide's interactions with sodium dodecyl sulfate micelles, a widely used bacterial membrane-mimicking environment. Throughout the simulation, the peptide was found to maintain its [Formula: see text]-helical conformation between residues Ile[Formula: see text]-Ala[Formula: see text], while adopting a position parallel to the surface to micelle, which is energetically-favourable due to many hydrophobic and electrostatic contacts with the micelle.
Topics: Amino Acid Sequence; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Antineoplastic Agents; Hydrophobic and Hydrophilic Interactions; Magnetic Resonance Spectroscopy; Membranes; Micelles; Molecular Dynamics Simulation; Protein Conformation, alpha-Helical; Sodium Dodecyl Sulfate; Static Electricity; Trifluoroethanol; Water
PubMed: 34789753
DOI: 10.1038/s41598-021-01769-3 -
Accounts of Chemical Research May 2021Biological membranes separate the interior of cells or cellular compartments from their outer environments. This barrier function of membranes can be disrupted by... (Review)
Review
Biological membranes separate the interior of cells or cellular compartments from their outer environments. This barrier function of membranes can be disrupted by membrane-active peptides, some of which can spontaneously penetrate through the membranes or open leaky transmembrane pores. However, the origin of their activity/toxicity is not sufficiently understood for the development of more potent peptides. To this day, there are no design rules that would be generally valid, and the role of individual amino acids tends to be sequence-specific.In this Account, we describe recent progress in understanding the design principles that govern the activity of membrane-active peptides. We focus on α-helical amphiphilic peptides and their ability to (1) translocate across phospholipid bilayers, (2) form transmembrane pores, or (3) act synergistically, i.e., to produce a significantly more potent effect in a mixture than the individual components.We refined the description of peptide translocation using computer simulations and demonstrated the effect of selected residues. Our simulations showed the necessity to explicitly include charged residues in the translocation description to correctly sample the membrane perturbations they can cause. Using this description, we calculated the translocation of helical peptides with and without the kink induced by the proline/glycine residue. The presence of the kink had no effect on the translocation barrier, but it decreased the peptide affinity to the membrane and reduced the peptide stability inside the membrane. Interestingly, the effects were mainly caused by the peptide's increased polarity, not the higher flexibility of the kink.Flexibility plays a crucial role in pore formation and affects distinct pore structures in different ways. The presence of a kink destabilizes barrel-stave pores, because the kink prevents the tight packing of peptides in the bundle, which is characteristic of the barrel-stave structure. In contrast, the kink facilitates the formation of toroidal pores, where the peptides are only loosely arranged and do not need to closely assemble. The exact position of the kink in the sequence further determines the preferred arrangement of peptides in the pore, i.e., an hourglass or U-shaped structure. In addition, we demonstrated that two self-associated (via termini) helical peptides could mimic the behavior of peptides with a helix-kink-helix motif.Finally, we review the recent findings on the peptide synergism of the archetypal mixture of Magainin 2 and PGLa peptides. We focused on a bacterial plasma membrane mimic that contains negatively charged lipids and lipids with negative intrinsic curvature. We showed that the synergistic action of peptides was highly dependent on the lipid composition. When the lipid composition and peptide/lipid ratios were changed, the systems exhibited more complex behavior than just the previously reported pore formation. We observed membrane adhesion, fusion, and even the formation of the sponge phase in this regime. Furthermore, enhanced adhesion/partitioning to the membrane was reported to be caused by lipid-induced peptide aggregation.In conclusion, the provided molecular insight into the complex behavior of membrane-active peptides provides clues for the design and modification of antimicrobial peptides or toxins.
Topics: Cell Membrane; Lipids; Peptides; Protein Conformation, alpha-Helical
PubMed: 33844916
DOI: 10.1021/acs.accounts.1c00047 -
International Journal of Molecular... May 2023Biomarker development, improvement, and clinical implementation in the context of kidney disease have been a central focus of biomedical research for decades. To this... (Review)
Review
Biomarker development, improvement, and clinical implementation in the context of kidney disease have been a central focus of biomedical research for decades. To this point, only serum creatinine and urinary albumin excretion are well-accepted biomarkers in kidney disease. With their known blind spot in the early stages of kidney impairment and their diagnostic limitations, there is a need for better and more specific biomarkers. With the rise in large-scale analyses of the thousands of peptides in serum or urine samples using mass spectrometry techniques, hopes for biomarker development are high. Advances in proteomic research have led to the discovery of an increasing amount of potential proteomic biomarkers and the identification of candidate biomarkers for clinical implementation in the context of kidney disease management. In this review that strictly follows the PRISMA guidelines, we focus on urinary peptide and especially peptidomic biomarkers emerging from recent research and underline the role of those with the highest potential for clinical implementation. The Web of Science database (all databases) was searched on 17 October 2022, using the search terms "marker *" OR biomarker * AND "renal disease" OR "kidney disease" AND "proteome *" OR "peptid *" AND "urin *". English, full-text, original articles on humans published within the last 5 years were included, which had been cited at least five times per year. Studies based on animal models, renal transplant studies, metabolite studies, studies on miRNA, and studies on exosomal vesicles were excluded, focusing on urinary peptide biomarkers. The described search led to the identification of 3668 articles and the application of inclusion and exclusion criteria, as well as abstract and consecutive full-text analyses of three independent authors to reach a final number of 62 studies for this manuscript. The 62 manuscripts encompassed eight established single peptide biomarkers and several proteomic classifiers, including CKD273 and IgAN237. This review provides a summary of the recent evidence on single peptide urinary biomarkers in CKD, while emphasizing the increasing role of proteomic biomarker research with new research on established and new proteomic biomarkers. Lessons learned from the last 5 years in this review might encourage future studies, hopefully resulting in the routine clinical applicability of new biomarkers.
Topics: Humans; Proteomics; Renal Insufficiency, Chronic; Kidney; Peptides; Biomarkers
PubMed: 37298105
DOI: 10.3390/ijms24119156 -
Journal of Peptide Science : An... Jan 2023Protein-protein interactions (PPI) are involved in all cellular processes and many represent attractive therapeutic targets. However, the frequently rather flat and... (Review)
Review
Protein-protein interactions (PPI) are involved in all cellular processes and many represent attractive therapeutic targets. However, the frequently rather flat and large interaction areas render the identification of small molecular PPI inhibitors very challenging. As an alternative, peptide interaction motifs derived from a PPI interface can serve as starting points for the development of inhibitors. However, certain proteins remain challenging targets when applying inhibitors with a competitive mode of action. For that reason, peptide-based ligands with an irreversible binding mode have gained attention in recent years. This review summarizes examples of covalent inhibitors that employ peptidic binders and have been tested in a biological context.
Topics: Peptides
PubMed: 36239115
DOI: 10.1002/psc.3457 -
Drug Delivery Dec 2023Peptides, as potential therapeutics continue to gain importance in the search for active substances for the treatment of numerous human diseases, some of which are, to... (Review)
Review
Peptides, as potential therapeutics continue to gain importance in the search for active substances for the treatment of numerous human diseases, some of which are, to this day, incurable. As potential therapeutic drugs, peptides have many favorable chemical and pharmacological properties, starting with their great diversity, through their high affinity for binding to all sort of natural receptors, and ending with the various pathways of their breakdown, which produces nothing but amino acids that are nontoxic to the body. Despite these and other advantages, however, they also have their pitfalls. One of these disadvantages is the very low stability of natural peptides. They have a short half-life and tend to be cleared from the organism very quickly. Their instability in the gastrointestinal tract, makes it impossible to administer peptidic drugs orally. To achieve the best pharmacologic effect, it is desirable to look for ways of modifying peptides that enable the use of these substances as pharmaceuticals. There are many ways to modify peptides. Herein we summarize the approaches that are currently in use, including lipidization, PEGylation, glycosylation and others, focusing on lipidization. We describe how individual types of lipidization are achieved and describe their advantages and drawbacks. Peptide modifications are performed with the goal of reaching a longer half-life, reducing immunogenicity and improving bioavailability. In the case of neuropeptides, lipidization aids their activity in the central nervous system after the peripheral administration. At the end of our review, we summarize all lipidized peptide-based drugs that are currently on the market.
Topics: Peptides; Lipids
PubMed: 38010881
DOI: 10.1080/10717544.2023.2284685 -
British Journal of Pharmacology Oct 2017The RFamide neuropeptide 26RFa was first isolated from the brain of the European green frog on the basis of cross-reactivity with antibodies raised against bovine... (Review)
Review
The RFamide neuropeptide 26RFa was first isolated from the brain of the European green frog on the basis of cross-reactivity with antibodies raised against bovine neuropeptide FF (NPFF). 26RFa and its N-terminally extended form glutamine RF-amide peptide (QRFP) have been identified as cognate ligands of the former orphan receptor GPR103, now renamed glutamine RF-amide peptide receptor (QRFP receptor). The 26RFa/QRFP precursor has been characterized in various mammalian and non-mammalian species. In the brain of mammals, including humans, 26RFa/QRFP mRNA is almost exclusively expressed in hypothalamic nuclei. The 26RFa/QRFP transcript is also present in various organs especially in endocrine glands. While humans express only one QRFP receptor, two isoforms are present in rodents. The QRFP receptor genes are widely expressed in the CNS and in peripheral tissues, notably in bone, heart, kidney, pancreas and testis. Structure-activity relationship studies have led to the identification of low MW peptidergic agonists and antagonists of QRFP receptor. Concurrently, several selective non-peptidic antagonists have been designed from high-throughput screening hit optimization. Consistent with the widespread distribution of QRFP receptor mRNA and 26RFa binding sites, 26RFa/QRFP exerts a large range of biological activities, notably in the control of energy homeostasis, bone formation and nociception that are mediated by QRFP receptor or NPFF2. The present report reviews the current knowledge concerning the 26RFa/QRFP-QRFP receptor system and discusses the potential use of selective QRFP receptor ligands for therapeutic applications.
Topics: Animals; Humans; Intercellular Signaling Peptides and Proteins; Neuropeptides; Peptides; Receptors, Neuropeptide
PubMed: 28613414
DOI: 10.1111/bph.13907