SCIENCE CHINA Chemistry • MINI REVIEWS •
doi: 10.1007/s11426-016-0186-x
· SPECIAL ISSUE · Dedicated to the 60th Anniversary of Institute of Chemistry, CAS
Rational design and functional evolution of targeted peptides for bioanalytical applications Yanyan Huang1,2, Yulong Jin1,2 & Rui Zhao1,2* 1
Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China 2 University of Chinese Academy of Sciences, Beijing 100049, China Received April 23, 2016; accepted July 10, 2016
The complicated, highly dynamic and diverse nature of biosystems brings great challenges to the specific analysis of molecular processes of interest. Nature provides antibodies for the specific recognition of antigens, which is a straight-forward way for targeted analysis. However, there are still limitations during the practical applications due to the big size of the antibodies, which accelerate the discovery of small molecular probes. Peptides built from various optional building blocks and easily achieved by chemical synthetic approaches with predictable conformations, are versatile and can act as tailor-made targeting vehicles. In this mini review, we summarize the recent developments in the discovery of novel peptides for bioanalytical and biomedical applications. Progresses in peptide-library design and selection strategies are presented. Recent achievements in the peptide-guided detection, imaging and disease treatment are also focused. peptide, design, screening, targeted analysis, biomedical applications
Citation:
Huang Y, Jin Y, Zhao R. Rational design and functional evolution of targeted peptides for bioanalytical applications. Sci China Chem, 2doi: 10.1007/ s11426-016-0186-x
Introduction 1 Understanding biological processes especially at the molecular level is crucial for the development of effective approaches for detection and regulation of disorders, which is fundamental for the benefit of human health [1]. The complicated, highly dynamic and multi-parameter nature of biological systems however brings great challenges, which call for selective, sensitive and reliable tools and methods. Tremendous research efforts have been devoted to the development of chemical agents and materials for the targetable detection, monitoring and functional modulation *Corresponding author (email:
[email protected])
© Science China Press and Springer-Verlag Berlin Heidelberg 2016
of biological events [2–4]. As the natural-occurring molecular recognition pair, the interaction between antibody and antigen provides a straightforward way for targeted analysis and treatment. However, the big size of the antibodies limits their penetration into cells, and possible immunogenicity response hampers the application in humans. The difficulties with synthesize and fragile character of antibodies also accelerate the search for new targeting molecules. By recognizing molecular signatures and physiological markers, small targeting vehicles including aptamers, peptides and vitamins have received extensive research interests [5,6]. Target-addressable analysis with the guidance of the specific bioprobes has been achieved in the fields of cell imaging, separation and disease treatment. To study the continuously growing number of uncovchem.scichina.com link.springer.com
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ered biomolecular interaction networks, smart and versatile targeting agents are urgently needed. Peptides, a small version of protein, are distinguished from proteins on the basis of size. Benefiting from the favorable biodistribution, cell penetrability and efficacy, peptide drugs and vaccines have been under extensive investigation [7], and many of them have been approved by FDA (the U.S. Food and Drug Administration) or used in clinical trials [8–11]. Moreover, peptides can be built from various optional building blocks and easily achieved by chemical synthetic approaches. With predictable conformations and high stability, peptides are versatile and can act as tailor-made targeting probes. Concerning the bioanalytical applications, peptides are tolerant towards chemical modifications, which allows the conjugation with functional moieties for signal reporting, such as enzymes, fluorescent dyes and cytotoxins. And a variety of conjugation chemistries including amides, carboxylic acid esters, thioethers can be provided for site-specific functionalization of peptides [12]. Therefore, the development of highly specific peptides becomes perspective for the detection, caption and tracing of molecular events in complicated biosystems. Given the biological relevance and significance of peptides, remarkable research efforts have been devoted to the design, screening and analytical applications of targeted peptides. Several excellent reviews have reported on the design of peptides [13], functional mining for biologically active peptides [14,15] and their applications in biosensing [16], targeted molecular imaging, disease diagnosis and
therapy [17–19]. Here, we summarize the recent achievements in design and identification of targeted peptides. The bioanalytical and biomedical applications of the peptides are also focused. The perspective of the peptides for targeted diagnostic and therapeutic treatments, as well as protein function manipulation is also discussed.
Rational 2 design of peptides/peptide libraries As an ideal targeted probe, the agent should possess high affinity towards the target molecules, specific binding and uptake, high stability and permeability [20]. Natural peptides provide a rich source for the development of peptide-based bioprobes. The progress in molecular biology allows the discovery of a growing number of disease-related targets in biosystems. To meet the wide range of application, artificial peptides are of great potential and highly desirable [13]. Peptide libraries from either chemical synthesis or biological expression are well-known as high-content sources for the discovery of novel peptide ligands [15] (Figure 1). Phage display random libraries provide a useful and practical access to prepare and identify peptides towards target molecules, including antibodies, receptors, enzymes/enzyme inhibitors and carbohydrates [21]. Recently, by using a phage-displayed random peptide library, immunoactive peptides towards immunoglobulin G (IgG) of tuberculosis patients were identified, which could serve as alternative serological antigens with improved accuracy for early detection of tuberculosis
Peptide Figure 1 libraries used for the selection of cell-binding peptides. Biological and chemical peptide libraries have been used to isolate cell specific peptides. For phage and bacterial display, the diversity is generated at the DNA level and there is an inherent genotype-phenotype connection. For one-bead one-compound and positional scanning synthetic peptide libraries (PS-SPCL), the diversity is generated chemically and is based on the use of a collection of monomers. The resultant peptides are displayed in red for clarity. The PS-SPCL schematic illustrates the pools of peptide libraries generated for a tetrameric peptide where each of the 20 amino acids is a unique colored circle and the mixture of 20 amino acids is shown in blue [15] (color online).
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[22]. The first screening of lignin-binding peptides using a phage display technique was also reported [23]. Research advance was also achieved in the field of combating antibiotic resistance. Three penicillinase-binding peptides were identified from a phage display library using the surface plasmon resonance approach [24]. Due to the biological origin, phage-displayed peptide library usually employs only the 20 natural amino acids. Synthetic peptide libraries compatible with unnatural amino acids, monosaccharides, nucleotides and lipids provide more choices for target-ligand design [14]. Among the various kinds of non-biological combinatorial libraries, one-bead one-compound libraries and positional scanning synthetic peptide libraries have been used for the selection of cell-binding peptides [15] (Figure 1), cancer-targeting peptides [14], and peptide vaccine [25]. To modulate protein-protein interactions (PPIs) central in the regulation of biological processes, Pei and co-workers [26] generated a combinatorial library of 5.7×106 bicyclic peptides and screened out a moderately potent and cell-permeable Κ-Ras inhibitor. By physically blocking the Ras-effector interactions, the peptide inhibits the downstream signaling events, and leads to apoptosis of the cancer cells [26]. As the library-synthetic approach is concerned, novel photochemical reaction was reported for the preparation of one-bead one-compound peptide libraries [27]. Based on the electrospray ionization technique, photosynthesis of a combinatorial peptide library in the gas phase was also realized [28]. Compared with the random libraries, more directional design holds distinct feature in significantly simplified but effective contents, which could facilitate the fast, accurate and economic identification of desired peptides. Based on the structures of the peptide binding epitopes derived from protein interaction sites, inhibitors targeting protein-protein interactions can be rationally designed by mimicking the secondary structure elements including turns, β-sheets and helices [29]. According to the known molecular recognition roles, directional design of small peptide libraries is also feasible and effective. Urbach and co-workers [30] reported a library screening of 105 peptides to the synthetic receptor cucurbit[8]uril (Q8) (Figure 2) in aqueous buffer. The idea for peptide design was built on the knowledge that Q8 interacts with peptides through N-terminal aromatic residues such as Trp, Phe, or Tyr [31]. The effect from the adjacent residues was examined by NMR spectroscopy, electrospray ionization mass spectrometry and isothermal titration calorimetry. A tripeptide Tyr-Leu-Ala with the equilibrium dissociation constant of 7.2 nM to Q8 was final obtained. Since the discovery that sense peptides and their corresponding antisense peptides interacts specifically, the rules for how individual amino acids interact serve as a widely applicable guidance for peptide design [32]. In our previous
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works, the degeneracy of antisense peptides was carefully investigated, which shows attractive potential for guided design of small peptide libraries [33–35]. After the first successful attempt in design peptide inhibitor for influenza virus A [36], degeneracy-based antisense peptide libraries were generated for the identification of peptides toward spike protein on coronavirus [37], interferon-β [34], and cancer-related proteins [35], which demonstrate significantly reduced workflow and high efficiency for tailoring affinity peptides (Figure 3).
Selection 3 of affinity peptides With the interest to investigate and interfere the molecular events in biosystems, peptide libraries with varied complexity have been constructed [13–15,30]. In order to identify an optimum peptide with high affinity and specificity towards the targets, efficient and robust approaches are essential to screening the libraries. The advances in computer science and analytical science facilitate the continuous development of novel selection methods for affinity peptides [38–40]. Protein crystal structures are usually the prerequisite for in silico peptide design and screening. Recently, Mitragotri and co-workers [38] developed a computational process for the identification of cyclic peptides with skin-penetrability independent of the knowledge of target structures. Besides in silico screening, the binding of the selected peptides to the targets keratin and cyclosporine A was further examined
Library Figure 2 screening of peptide for cucurbit[8]uril (Q8) [31] (color online).
Design Figure 3 of degeneracy-based antisense peptide libraries (color online).
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by affinity chromatography and mass spectrometry. Although the computational screening shows distinct advantages in rapidness, economic in labor and experimental expense, there is still the need to testify the binding behavior of the screened peptides by experiments [39]. By using both bioinformatics-based molecular simulations and a label-free photonic crystal biosensor, Ye and co-workers [40] screened out four peptides from phage display libraries for the interaction with toxin FvTox1. Analytical methods such as fluorescent spectroscopy, chromatography, mass spectrometry and microfluidic technique have been widely applied for the selection of bioactive peptides [14,36,41,42]. To facilitate the screening and identification process, chemical tags are usually used to label peptide candidates, such as fluorophores and nano/micro particles, which may interfere with the molecular interactions between peptides and targets. Therefore, screening approaches operate in a label-free mode are always appealing. By using hydrogen exchange mass spectrometry, a label-free, in-solution screening method was reported. The idea is based on the phenomenon of decreased amide hydrogen exchange by peptides upon binding to the target [41]. By monitoring the peptide-protein interactions using mass spectrometry, peptides were screening out towards human calmodulin and bovine ribonuclease respectively. To address the challenge of in vitro selection of chemically modified peptide libraries presented on phage, Derda and co-workers [43] generated phage-displayed peptide libraries using unique combinations of codons. Their results show that specific chemical post-translational modifications are significantly enriched in panning against the specific targets. Since the first application of microfluidic chip for biomolecular screening [44], “lab on a chip” provides an attractive platform for ligand screening featuring in integration, automation, high-efficiency, high-throughput and low consumption. In our previous work, integrated continuous-flow microfluidic systems were designed and fabricated for solid phase peptide synthesis and peptide affinity screening (Figure 4). During peptide synthesis, the
microfluidic system was composed of a glass-based radial reaction chip, a diffluent chip, amino acid feeding reservoirs and continuous-flow reagent pathways. Peptides from an antibody affinity peptide library against β-endorphin were obtained simultaneously in high quality within a short time [45]. To integrate peptide screening with in situ detection, a tetra-layer microfluidic hybrid chip containing two top eccentric diffluent layers, an inter-layer and a bottom screening layer, was developed. The incorporation of eccentric diffluent layers eliminated the use of excessive accessories and complicated pipelines usually used in other systems. The pH gradient generators allowed simultaneous screening of peptides under different pH conditions. The affinities of the peptide ligands to β-endorphin antibody were conveniently assessed by on-chip confocal detection [46]. The results show that the integrated sample introduction, bead-based ligand screening and on-chip detection can be achieved on a low-cost and easy-to-use microfluidic screening system. Recently, a bi-functional microarray was fabricated for the screening of one-bead one-compound peptide library towards the epithelial cell adhesion molecule (EpCAM). Capable of in situ sequencing and in situ affinity detection, the on-chip system identified peptides for hunting circulating tumor cells (CTCs) from blood samples [42]. With the recognition that a great number of target biomolecules are anchored in cell membrane or exist inside cells, selecting affinity ligands at the cell level rather than in solution becomes highlighted [47]. Kim and co-workers [48] presented a novel high-throughput pooled screening approach to select inhibitors of PPIs in cells. In this work, the screen reveals both new drug targets and peptide drug leads by cell-based biopanning approach. The recent development in oriented circular dichroism provides a powerful tool for charactering the effect of lipid bilayer to peptide conformation, which can assist the screening of membrane-active peptides [49]. To discover peptides with in vivo biological functions, screening carried out in vivo may be more direct and effective. A novel cyclic peptide was selected from phage display libraries using an animal experimental model.
(a) Figure 4 Radial peptide synthesis microfluidic system; (b) design of the peptide screening microfluidic chip and fluoroimmunoassay scheme in the screening chamber [45,46] (color online).
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The screened peptide can be rapidly transported across the intestinal mucosa and target distinct intestinal cells, which is promising for delivering drugs for disease treatment [50].
Bioanalytical 4 and biomedical applications Screened peptides with high affinity and specificity towards targets receive remarkable attentions from basic research areas, drug discovery and clinical applications. To fulfill their analytical and biological functions, target peptides can be either used in its native form or modified with signal reporters, toxins and nanomaterial. Peptide assembled nanomaterial shows great potential in regenerative medicine [51], nanosensors and nanodevices [52,53]. There are valuable review articles comprehensively summarizing peptide-based fluorescence biosensors [16], molecular imaging and disease diagnosis [17,20], as well as therapeutics [18]. Detection and manipulation of microorganisms are hot topics of peptide research [54]. A decamer peptide was recently selected for the binding to Candida albicans. It is interesting to find that this peptide can differentiate the forms of C. albicans cells. It interacts the mature hyphal form more efficiently than their yeast form [55]. By screening a hemagglutinin fragment peptide library, a peptide with effective antiviral activity against both human and avian influenza viral was obtained. Mechanism investigation indicated that the peptide binds to sialyllactose and blocks the entry of influenza virus to host cells [56]. This peptide might be a potent drug candidate for influenza treatment. Lipopolysaccharide (LPS) released from Gram-negative bacteria is directly related with the life-threatening septic shock. Liedberg and co-workers [57] recently developed a LPS sensor by assembling peptide on graphene oxide (Figure 5). The fluorescence of the dye was controlled by the specific recognition of the peptide to LPS. This fluorescence turn-on sensor offered a very low detection limit of 130 pM. Benefiting from its high selectivity and sensitivity, the sensor was applied for the detection of LPS from different bacterial strains as well as LPS on the
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membrane of living E. coli. Exploring the molecular events in mammalian cell is crucial for disease analysis and treatment. The usage of peptides in this area also achieves significant progress. The review on mining for cell-binding peptides gives thorough and impressive overview of the isolation and application of peptides for different cells [15]. To overcome the difficulty of exogenous agents in entering cells, cell penetrating peptides (CPPs) play an important role in transporting different cargoes into cells [58]. An intrinsically disordered peptide was reported by Schneider and co-workers [59], which crosses cellular membranes via non-endosomal mechanism. Together with high biocompatibility and stability, the peptide can be used for the delivery of drug candidates directly to the cytoplasma of different cells (Figure 6). The problem in the inefficient delivery of proteins into mammalian cells severe limits the therapeutic outcomes of many proteins. To address this, a peptide capable of enhances endosomal escape of delivered proteins was discovered and characterized. By fused to superpositively charged green fluorescent protein (GFP), the delivery of cationic proteins was successfully realized both in vitro and in vivo [60]. With the aim of analyzing membrane transporter directly in cells, a peptide developed from reversed-footprinting mass spectrometry was employed as a structural marker. By reporting the structure of cystic fibrosis transmembrane conductance regulator (CFTR), the peptide can facilitate the directly investigation of the structure-function relations of proteins in their endogenous cellular locations [61]. To explore the physical properties of cell-cell and cell-extracellular matrix, Salaita and co-workers [62] generated a small library of tension probes based on the interaction between peptides and integrin and cadherin receptors. They achieved for the first time the long-term imaging of molecular tension. Cancer with high morbidity and mortality poses a great threat to human health. Research efforts have been exerted towards the development of peptide-based agents for the detection and ablation of cancer cells. By using the proapoptosis
(a) Figure 5 Structure of LPS and (b) sensing principle of the peptide-GO-assembled LPS sensor, including attachment of fluorescence labelled peptide on GO and subsequent detachment of the peptide triggered by LPS [57] (color online).
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(a–c) Figure 6 Top: live-cell imaging of HeLa cells as a function of time after addition of 10 μm fluorescein-labeled CLIP6 peptide (scale bar=10 μm). Associated z-stacks are also shown. Bottom: percentage of total cellular fluorescence measured at the membrane, within the cytoplasm or localized at the nucleus. Mechanism of CLIP6 (d) or TAT (e) uptake into A549, HeLa, or OVCAR-3 cells was assessed after a 1 h incubation with 10 μM of peptide alone (control, gray bars), under ATP depletion (open bars), or with hyperosmolar sucrose (black bars) preconditioning. Uptake results under ATP depletion and hyperosmolar sucrose conditions were compared to direct peptide incubation (gray bars) to determine statistical significance, denoted by * p≤0.05, or ** p≤0.01 [59] (color online).
peptide, Zhang and co-worker [63] developed a self-delivery system. Owing to the mitochondrial targeting ability of the peptide, in situ generation of reactive oxygen species in mitochondria was obtained and led to cancer cell death. Recently, Yan and co-workers [64] reported the usage of peptide-tuned self-assembly of functional components for the photodynamic therapy of cancer. Only with a single drug dose and a single exposure to light, tumor in mice was almost completely eliminated. By the combination of antisense peptide approach and affinity chromatographic screening, an optimal peptide AP2H with high affinity towards an extracellular fragment of a tumor-related protein LAPTM4B was rationally designed and efficiently evolved in our group [35]. Capable of discriminating the expression level of LAPTM4B protein and low-pH microenvironment of cancer cells, AP2H guided the discrimination and detection of cancerous cells from normal cells. The high selectivity and sensitivity of the peptide enabled tracking the translocation of LAPTM4B from plasma membrane to lysosomes. The employment of AP2H as an actively targeting moiety, peptide-stamped delivery systems were developed for the imaging-guided photodynamic therapy of cancer cells (Figure 7) [65,66]. To address the side effects of conventional anticancer drugs, a peptide-based pH-sensitive drug delivery system was also developed. Being responsive to LAPTM4B protein and tumor acidosis, intracellular drug release and activation were achieved for cancerous cells, while normal cells kept unaffected [67]. As the practical application of peptides are concerned, the
incorporation of nanomaterial and multivalent dendrimer brings the benefit of higher biostability and bioavailability, which shows advantages in cell sensing, imaging, drug delivery and therapeutics [19,68,69]. Based on the recognition of the well-known cyclic peptide containing arginine-glycine-aspartic acid sequence to integrin, peptide-decorated fluorescent silicon nanoparticles were designed and prepared. The specific imaging and destruction of cancer cells were realized simultaneous [70]. Recently, polymer nanoparticles loaded with paclitaxel (PTX) were grafted with the peptide for targeted drug delivery and retention in tumor. The peptide was designated to introduce hydrophilic moiety and enzyme-responsive ability of the nanoparticles. The resultant targetable nanomedicine showed enhanced safety and efficacy (Figure 8) [71]. Inspired by polyvalency which is found ubiquitously in nature, multivalent peptides and peptide dentrimers are designed for a wide range of applications [72]. Based on the characteristics of dendritic peptides in monodispersity, welldefined structure and rich functional groups, novel therapeutic dendrimers were reported for the supermolecular interaction with DNA and tumor inhibition [73]. Multivalent display is also demonstrated to increase the efficacy of the peptide compared to its monomer form [74]. Kolmar and co-workers [75] generated a multivalent constructs by covalently binding multiple copies of peptide to biomolecular scaffolds. Owing to the recognition of the peptide to death receptor 5, heptameric constructs with proper inter-ligand distance, spatial orientation and peptide copy number showed significant
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Peptide-guided Figure 7 bioimaging and photodynamic therapy of cancer cells [66] (color online).
Nanoparticles Figure 8 assemble, and subsequently change morphology in response to matrix metalloproteinases (MMP) [71] (color online).
apoptosis-inducing ability.
Conclusions 5 In recent years, tremendous advances have been made towards the development of affinity peptides for bioanalytical and biomedical applications. The fast expansion is not only attributed to the effective design of peptide libraries, but also arises from the continuous appearance of robust selection methods. For peptide libraries, phage display and combinatorial chemical approaches provides rich and varied candidates. Small libraries rationally designed based on known molecular interaction roles afford new sources for peptide discovery. On the other hand, selection protocols also become more powerful including both chemical and biological methods, which make the identification process economic in both time and labor. However, there is also a notion that peptides selected from libraries should be further optimized, so as to obtain high affinity, specificity and activity [15]. The effectiveness of peptides has been demonstrated by the ongoing applications of many isolated peptides for clinical use or pre-clinical tests. The peptides discussed in this review have displayed their efficacy in target detection, imaging and functional investigation. The combination of peptides with nanomaterial, functional polymer and organic compounds opens a
broad path for new practical applications, which could facilitate the translation of the peptides into effective diagnostics and therapeutics. This Acknowledgments work was supported by the National Natural Science Foundation of China (21375134, 21475140, 21135006, 21321003), The National Basic Research Program of China (2015CB856300) and the Chinese Academy of Sciences. The authors declare that they have no conflict of Conflict of interest interest. 1
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