Abstract
Peptides provide promising templates for developing drugs to occupy a middle space between small molecules and antibodies and for targeting ‘undruggable’ intracellular protein–protein interactions. Importantly, rational or in cerebro design, especially when coupled with validated in silico tools, can be used to efficiently explore chemical space and identify islands of ‘drug-like’ peptides to satisfy diverse drug discovery program objectives. Here, we consider the underlying principles of and recent advances in rational, computer-enabled peptide drug design. In particular, we consider the impact of basic physicochemical properties, potency and ADME/Tox opportunities and challenges, and recently developed computational tools for enabling rational peptide drug design. Key principles and practices are spotlighted by recent case studies. We close with a hypothetical future case study.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1 . Peptide therapeutics: current status and future directions. Drug Discov. Today 20(1), 122–128 (2015).Crossref, Medline, CAS, Google Scholar
- 2 . Future directions for peptide therapeutics development. Drug Discov. Today 18(17–18), 807–817 (2013).Crossref, Medline, CAS, Google Scholar
- 3 . Construction and screening of vast libraries of natural product-like macrocyclic peptides using in vitro display technologies. Curr. Opin. Chem. Biol. 24, 131–138 (2015).Crossref, Medline, CAS, Google Scholar
- 4 . Screening bicyclic peptide libraries for protein-protein interaction inhibitors: discovery of a tumor necrosis factor-alpha antagonist. J. Am. Chem. Soc. 135(32), 11990–11995 (2013).Crossref, Medline, CAS, Google Scholar
- 5 . High-resolution view of compound promiscuity. F1000 Research 2, 144 (2013).Crossref, Medline, Google Scholar
- 6 . Multi-objective optimization methods in drug design. Drug Discov. Today Technol. 10(3), e427–e435 (2013).Crossref, Medline, Google Scholar
- 7 Discovery of a potent stapled helix peptide that binds to the 70N domain of replication protein A. J. Med. Chem. 57(6), 2455–2461 (2014).Crossref, Medline, CAS, Google Scholar
- 8 . EphB receptor-binding peptides identified by phage display enable design of an antagonist with ephrin-like affinity. J. Biol. Chem. 280(17), 17301–17311 (2005).Crossref, Medline, CAS, Google Scholar
- 9 Elucidation of the contribution of active site and exosite interactions to affinity and specificity of peptidylic serine protease inhibitors using non-natural arginine analogs. Mol. Pharmacol. 80(4), 585–597 (2011).Crossref, Medline, CAS, Google Scholar
- 10 A specific STAT3-binding peptide exerts antiproliferative effects and antitumor activity by inhibiting STAT3 phosphorylation and signaling. Cancer Res. 74(8), 2144–2151 (2014).Crossref, Medline, CAS, Google Scholar
- 11 . In silico and in vitro elucidation of BH3 binding specificity toward Bcl-2. Biochemistry 51(29), 5841–5850 (2012).Crossref, Medline, CAS, Google Scholar
- 12 Toxin acidic residue evolutionary function-guided design of de novo peptide drugs for the immunotherapeutic target, the Kv1.3 channel. Sci. Rep. 5, 9881 (2015).Crossref, Medline, CAS, Google Scholar
- 13 . Peptide bicycles that inhibit the Grb2 SH2 domain. ChemBioChem 13(10), 1490–1496 (2012).Crossref, Medline, CAS, Google Scholar
- 14 Creating protein affinity reagents by combining peptide ligands on synthetic DNA scaffolds. J. Am. Chem. Soc. 131(47), 17233–17241 (2009).Crossref, Medline, CAS, Google Scholar
- 15 Discovery of high-affinity protein binding ligands--backwards. PLoS ONE 5(5), e10728 (2010).Crossref, Medline, Google Scholar
- 16 A rationally engineered anti-HIV peptide fusion inhibitor with greatly reduced immunogenicity. Antimicrob. Agents Chemother. 57(2), 679–688 (2013).Crossref, Medline, CAS, Google Scholar
- 17 . Anaphylaxis and hypotension after administration of peginesatide. N. Engl. J. Med. 370(21), 2055–2056 (2014).Crossref, Medline, Google Scholar
- 18 . Protease-resistant peptide design-empowering nature's fragile warriors against HIV. Biopolymers 98(5), 431–442 (2012).Crossref, Medline, CAS, Google Scholar
- 19 . Phage selection of cyclic peptide antagonists with increased stability toward intestinal proteases. Protein Eng. Des. Sel. 26(1), 81–89 (2013).Crossref, Medline, CAS, Google Scholar
- 20 . Increased resistance of peptides to serum proteases by modification of their amino groups. Z. Naturforsch. 58(7–8), 558–561 (2003).Crossref, Medline, CAS, Google Scholar
- 21 . Serum stabilities of short tryptophan- and arginine-rich antimicrobial peptide analogs. PLoS ONE 5(9), (2010).Crossref, Google Scholar
- 22 A general method for making peptide therapeutics resistant to serine protease degradation: application to dipeptidyl peptidase IV substrates. J. Med. Chem. 56(21), 8339–8351 (2013).Crossref, Medline, CAS, Google Scholar
- 23 . Hydrocarbon-stapled peptides: principles, practice, and progress. J. Med. Chem. 57(15), 6275–6288 (2014).Crossref, Medline, CAS, Google Scholar
- 24 Serum stable natural peptides designed by mRNA display. Sci. Rep. 4, 6008 (2014).•• Shows how the rational use of phage display and natural amino acids can be used to optimize the proteolytic and serum stability of peptides without compromising potency.Crossref, Medline, CAS, Google Scholar
- 25 . Bioactive peptides: a review. Int. J. Bioautomation 15(4), 223–250 (2011).CAS, Google Scholar
- 26 . Peptide therapeutics: targeting the undruggable space. Eur. J. Med. Chem. 94, 459–470 (2015).Crossref, Medline, CAS, Google Scholar
- 27 . Relationships between structure and high-throughput screening permeability of peptide derivatives and related compounds with artificial membranes: application to prediction of Caco-2 cell permeability. Bioorg. Med. Chem. 12(1), 257–264 (2004).Crossref, Medline, CAS, Google Scholar
- 28 . Conformational flexibility, internal hydrogen bonding, and passive membrane permeability: successful in silico prediction of the relative permeabilities of cyclic peptides. J. Am. Chem. Soc. 128(43), 14073–14080 (2006).Crossref, Medline, CAS, Google Scholar
- 29 . Testing the conformational hypothesis of passive membrane permeability using synthetic cyclic peptide diastereomers. J. Am. Chem. Soc. 128(8), 2510–2511 (2006).Crossref, Medline, CAS, Google Scholar
- 30 On-resin N-methylation of cyclic peptides for discovery of orally bioavailable scaffolds. Nat. Chem. Biol. 7(11), 810–817 (2011).Crossref, Medline, CAS, Google Scholar
- 31 . Predicting and improving the membrane permeability of peptidic small molecules. J. Med. Chem. 55(7), 3163–3169 (2012).Crossref, Medline, CAS, Google Scholar
- 32 Optimizing PK properties of cyclic peptides: the effect of side chain substitutions on permeability and clearance. MedChemComm 3(10), 1282–1289 (2012).Crossref, Medline, CAS, Google Scholar
- 33 Probing the physicochemical boundaries of cell permeability and oral bioavailability in lipophilic macrocycles inspired by natural products. J. Med. Chem. 58(11), 4581–4589 (2015).Crossref, Medline, CAS, Google Scholar
- 34 Cell-permeable cyclic peptides from synthetic libraries inspired by natural products. J. Am. Chem. Soc. 137(2), 715–721 (2015).Crossref, Medline, CAS, Google Scholar
- 35 Exploring experimental and computational markers of cyclic peptides: charting islands of permeability. Eur. J. Med. Chem. 97, 202–213 (2015).Crossref, Medline, CAS, Google Scholar
- 36 . Quantitative comparison of the relative cell permeability of cyclic and linear peptides. Chem. Biol. 14(6), 671–677 (2007).Crossref, Medline, CAS, Google Scholar
- 37 . X-ray structure of a monomeric cyclophilin A-cyclosporin A crystal complex at 2.1 A resolution. J. Mol. Biol. 234(4), 1119–1130 (1993).Crossref, Medline, CAS, Google Scholar
- 38 Physiochemical drug properties associated with in vivo toxicological outcomes. Bioorg. Med. Chem. Lett. 18(17), 4872–4875 (2008).Crossref, Medline, CAS, Google Scholar
- 39 . A conformation of cyclosporin A in aqueous environment revealed by the X-ray structure of a cyclosporin-Fab complex. Science 256(5053), 92–94 (1992).Crossref, Medline, CAS, Google Scholar
- 40 Coadministration of a tumor-penetrating peptide enhances the efficacy of cancer drugs. Science 328(5981), 1031–1035 (2010).•• Shows that a small peptide motif can be used to transport a small molecule, another peptide or an antibody into cancer cells via the neuropillin pathway. This demonstrates the potential for peptides to be engineered to exploit cellular transport mechanisms to solve ADME problems.Crossref, Medline, CAS, Google Scholar
- 41 Transtumoral targeting enabled by a novel neuropilin-binding peptide. Oncogene 31(33), 3754–3763 (2012).Crossref, Medline, CAS, Google Scholar
- 42 De novo design of a tumor-penetrating peptide. Cancer Res. 73(2), 804–812 (2013).Crossref, Medline, CAS, Google Scholar
- 43 . Tumor-penetrating peptides. Front. Oncol. 3, 216 (2013).Crossref, Medline, Google Scholar
- 44 An endocytosis pathway initiated through neuropilin-1 and regulated by nutrient availability. Nat. Commun. 5, 4904 (2014).Crossref, Medline, CAS, Google Scholar
- 45 Tumor-penetrating iRGD peptide inhibits metastasis. Mol. Cancer Ther. 14(1), 120–128 (2015).Crossref, Medline, CAS, Google Scholar
- 46 Increased expression of neuropilin 1 in melanoma progression and its prognostic significance in patients with melanoma. Mol. Med. Rep. 12(2), 2668–2676 (2015).Crossref, Medline, CAS, Google Scholar
- 47 Vascular endothelial growth factor is an autocrine growth factor, signaling through neuropilin-1 in non-small cell lung cancer. Mol. Cancer 14(1), 45 (2015).Crossref, Medline, Google Scholar
- 48 . Increased expression of neuropilin 1 is associated with epithelial ovarian carcinoma. Mol. Med. Rep. 12(2), 2114–2120 (2015).Crossref, Medline, CAS, Google Scholar
- 49 . Novel expression of Neuropilin 1 on human tumor-infiltrating lymphocytes in colorectal cancer liver metastases. Expert Opin. Ther. Targets 19(2), 147–161 (2015).Crossref, Medline, CAS, Google Scholar
- 50 . Transferrin receptor-mediated endocytosis: a useful target for cancer therapy. J. Membrane Biol. 247(4), 291–307 (2014).Crossref, Medline, CAS, Google Scholar
- 51 . Combination of amino acid/dipeptide with nitric oxide donating oleanolic acid derivatives as PepT1 targeting antitumor prodrugs. J. Med. Chem. 57(3), 1116–1120 (2014).Crossref, Medline, CAS, Google Scholar
- 52 . PepT1, ASBT-linked prodrug strategy to improve oral bioavailability and tissue targeting distribution. Curr. Drug Metabol. 16(1), 71–83 (2015).Crossref, Medline, Google Scholar
- 53 . Targeting L-type amino acid transporter 1 for anticancer therapy: clinical impact from diagnostics to therapeutics. Expert Opin. Ther. Targets
doi:10.1517/14728222.2015.1044975 (2015) (Epub ahead of print).Crossref, Medline, Google Scholar - 54 . TumorHoPe: a database of tumor homing peptides. PLoS ONE 7(4), e35187 (2012).Crossref, Medline, CAS, Google Scholar
- 55 . Oral delivery of the appetite suppressing peptide hPYY(3–36) through the vitamin B12 uptake pathway. J. Med. Chem. 54(24), 8707–8711 (2011).Crossref, Medline, CAS, Google Scholar
- 56 . Synthesis, characterization and pharmacodynamics of vitamin-B12-conjugated glucagon-like peptide-1. ChemMedChem 8(4), 582–586 (2013).Crossref, Medline, CAS, Google Scholar
- 57 . Transferrin and transferrin receptor function in brain barrier systems. Cell. Mol. Neurobiol. 20(1), 77–95 (2000).Crossref, Medline, CAS, Google Scholar
- 58 Systemic combinatorial peptide selection yields a non-canonical iron-mimicry mechanism for targeting tumors in a mouse model of human glioblastoma. J. Clin. Invest. 121(1), 161 (2011).Crossref, Medline, CAS, Google Scholar
- 59 Identification and design of peptides as a new drug delivery system for the brain. J. Pharmacol. Exp. Ther. 324(3), 1064–1072 (2008).Crossref, Medline, CAS, Google Scholar
- 60 Conjugation of a brain-penetrant peptide with neurotensin provides antinociceptive properties. J. Clin. Invest. 124(3), 1199 (2014).Crossref, Medline, CAS, Google Scholar
- 61 Antitumour activity of ANG1005, a conjugate between paclitaxel and the new brain delivery vector Angiopep-2. Br. J. Pharmacol. 155(2), 185–197 (2008).Crossref, Medline, CAS, Google Scholar
- 62 Transvascular delivery of small interfering RNA to the central nervous system. Nature 448(7149), 39–43 (2007).Crossref, Medline, CAS, Google Scholar
- 63 Targeting caspase-3 as dual therapeutic benefits by RNAi facilitating brain-targeted nanoparticles in a rat model of Parkinson's disease. PLoS ONE 8(5), e62905 (2013).Crossref, Medline, CAS, Google Scholar
- 64 . Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat. Biotechnol. 29(4), 341–345 (2011).Crossref, Medline, CAS, Google Scholar
- 65 Targeted brain delivery of itraconazole via RVG29 anchored nanoparticles. J. Drug Target. 19(3), 228–234 (2011).Crossref, Medline, CAS, Google Scholar
- 66 Brainpeps: the blood-brain barrier peptide database. Brain Struct. Funct. 217(3), 687–718 (2012).Crossref, Medline, Google Scholar
- 67 . Development of a Peptide-derived orally-active kappa-opioid receptor agonist targeting peripheral pain. Open Med. Chem. J. 7, 16–22 (2013).Crossref, Medline, CAS, Google Scholar
- 68 Probing the physicochemical boundaries of cell permeability and oral bioavailability in lipophilic macrocycles inspired by natural products. J. Med. Chem. 58(11), 4581–4589 (2015).Crossref, Medline, CAS, Google Scholar
- 69 Improving on nature: making a cyclic heptapeptide orally bioavailable. Angew. Chem. Int. Ed. Engl. 53(45), 12059–12063 (2014).Crossref, Medline, CAS, Google Scholar
- 70 Synthesis and structure-activity relationships of an orally available and long-acting analgesic peptide, N(alpha)-amidino-Tyr-D-Arg-Phe-MebetaAla-OH (ADAMB). J. Med. Chem. 45(23), 5081–5089 (2002).Crossref, Medline, CAS, Google Scholar
- 71 Backbone cyclic peptidomimetic melanocortin-4 receptor agonist as a novel orally administrated drug lead for treating obesity. J. Med. Chem. 51(4), 1026–1034 (2008).Crossref, Medline, CAS, Google Scholar
- 72 . Clinically significant drug interactions with cyclosporin. An update. Clin. Pharmacokinet. 30(2), 141–179 (1996).Crossref, Medline, CAS, Google Scholar
- 73 . Computer-aided antibody design. Protein Eng. Des. Sel. 25(10), 507–521 (2012).Crossref, Medline, CAS, Google Scholar
- 74 . Docking small peptides remains a great challenge: an assessment using AutoDock Vina. Brief Bioinform.
doi:10.1093/bib/bbv008 (2015) (Epub ahead of print).Crossref, Medline, Google Scholar - 75 . Empirical estimation of local dielectric constants: toward atomistic design of collagen mimetic peptides. Biopolymers 104(4), 360–370 (2015).Crossref, Medline, CAS, Google Scholar
- 76 . Recent work in the development and application of protein-peptide docking. Future Med. Chem. 4(12), 1619–1644 (2012).Link, CAS, Google Scholar
- 77 . Four small puzzles that Rosetta doesn't solve. PLoS ONE 6(5), e20044 (2011).Crossref, Medline, CAS, Google Scholar
- 78 TumorHoPe – Tumor Homing Peptide Database. http://crdd.osdd.net/raghava/tumorhope.Google Scholar
- 79 . Drug-permeability and transporter assays in Caco-2 and MDCK cell lines. Future Med. Chem. 3(16), 2063–2077 (2011).Link, CAS, Google Scholar
- 80 Brainpeps. http://brainpeps.ugent.be.Google Scholar
- 81 . Development of an informatics platform for therapeutic protein and peptide analytics. J. Chem. Inform. Model. 53(10), 2774–2779 (2013).Crossref, Medline, CAS, Google Scholar
- 82 Altoris - SARvision. www.chemapps.com/sarvision-biologics.Google Scholar
- 83 . PEP-FOLD: an updated de novo structure prediction server for both linear and disulfide bonded cyclic peptides. Nucleic Acids Res. 40, W288–W293 (2012).•• Describes the use of PEP-fold to predict peptide structures. Suggests that computational methods can be used to accurately model peptide structures and that future improvements will crucially depend on improvements in scoring.Crossref, Medline, CAS, Google Scholar
- 84 PEP-FOLD Server. http://bioserv.rpbs.univ-paris-diderot.fr/services/PEP-FOLD.Google Scholar
- 85 PepX: a structural database of non-redundant protein-peptide complexes. Nucleic Acids Res. 38, D545–D551 (2010).Crossref, Medline, CAS, Google Scholar
- 86 PepX. www.switchlab.org/bioinformatics/pepx.Google Scholar
- 87 . PepBind: a comprehensive database and computational tool for analysis of protein-peptide interactions. Genomics Proteomics Bioinform. 11(4), 241–246 (2013).Crossref, Medline, Google Scholar
- 88 PepBind. http://pepbind.bicpu.edu.in.Google Scholar
- 89 . The structural basis of peptide-protein binding strategies. Structure 18(2), 188–199 (2010).Crossref, Medline, CAS, Google Scholar
- 90 . Rosetta FlexPepDock web server--high resolution modeling of peptide-protein interactions. Nucleic Acids Res. 39, W249–W253 (2011).Crossref, Medline, CAS, Google Scholar
- 91 FlexPepDock. http://flexpepdock.furmanlab.cs.huji.ac.il.Google Scholar
- 92 . Rosetta FlexPepDock ab-initio: simultaneous folding, docking and refinement of peptides onto their receptors. PLoS ONE 6(4), e18934 (2011).Crossref, Medline, CAS, Google Scholar
- 93 . PaFlexPepDock: parallel ab-initio docking of peptides onto their receptors with full flexibility based on Rosetta. PLoS ONE 9(5), e94769 (2014).Crossref, Medline, Google Scholar
- 94 . AnchorDock: blind and flexible anchor-driven peptide docking. Structure 23(5), 929–940 (2015).Crossref, Medline, CAS, Google Scholar
- 95 . A unified conformational selection and induced fit approach to protein-peptide docking. PLoS ONE 8(3), e58769 (2013).• Provides a good discussion of many aspects of docking peptides that need to be considered to obtain accurate results.Crossref, Medline, CAS, Google Scholar
- 96 HADDOCK. http://haddocking.org.Google Scholar
- 97 . CABS-dock web server for the flexible docking of peptides to proteins without prior knowledge of the binding site. Nucleic Acids Res. 43(W1), W419–W424 (2015).Crossref, Medline, CAS, Google Scholar
- 98 CABS-Dock. http://biocomp.chem.uw.edu.pl/CABSdock.Google Scholar
- 99 . GalaxyPepDock: a protein-peptide docking tool based on interaction similarity and energy optimization. Nucleic Acids Res. 43(W1), W431–W435 (2015).Crossref, Medline, CAS, Google Scholar
- 100 GalaxyPepDock. http://galaxy.seoklab.org/cgi-bin/submit.cgi?type=PEPDOCK.Google Scholar
- 101 . Predicting peptide binding sites on protein surfaces by clustering chemical interactions. J. Comput. Chem. 36(1), 49–61 (2015).Crossref, Medline, CAS, Google Scholar
- 102 . Protein-peptide complex prediction through fragment interaction patterns. Structure 21(5), 789–797 (2013).Crossref, Medline, CAS, Google Scholar
- 103 . PEP-SiteFinder: a tool for the blind identification of peptide binding sites on protein surfaces. Nucleic Acids Res. 42, W221–W226 (2014).Crossref, Medline, CAS, Google Scholar
- 104 PEP-Site Finder. http://bioserv.rpbs.univ-paris-diderot.fr/services/PEP-SiteFinder.Google Scholar
- 105 . VitAL: Viterbi algorithm for de novo peptide design. PLoS ONE 5(6), e10926 (2010).Crossref, Medline, Google Scholar
- 106 . Exploring protein-peptide binding specificity through computational peptide screening. PLoS Comput. Biol. 9(10), e1003277 (2013).Crossref, Medline, Google Scholar
- 107 . Novel peptide-specific quantitative structure-activity relationship (QSAR) analysis applied to collagen IV peptides with antiangiogenic activity. J. Med. Chem. 54(19), 6492–6500 (2011).Crossref, Medline, CAS, Google Scholar
- 108 . Recent advances in QSAR and their applications in predicting the activities of chemical molecules, peptides and proteins for drug design. Curr. Protein Peptide Sci. 9(3), 248–260 (2008).Crossref, Medline, CAS, Google Scholar
- 109 . Two-level QSAR network (2L-QSAR) for peptide inhibitor design based on amino acid properties and sequence positions. SAR QSAR Environ. Res. 25(10), 837–851 (2014).Crossref, Medline, CAS, Google Scholar
- 110 . Predicting the affinity of epitope-peptides with class I MHC molecule HLA-A*0201: an application of amino acid-based peptide prediction. Protein Eng. Des. Sel. 20(9), 417–423 (2007).Crossref, Medline, CAS, Google Scholar
- 111 . Recent development of Peptide drugs and advance on theory and methodology of Peptide inhibitor design. Med. Chem. 11(3), 235–247 (2015).Crossref, Medline, CAS, Google Scholar
- 112 . A brief overview of antimicrobial peptides containing unnatural amino acids and ligand-based approaches for peptide ligands. Curr. Top. Med. Chem. 13(24), 3205–3224 (2013).Crossref, Medline, CAS, Google Scholar
- 113 Machine learning assisted design of highly active peptides for drug discovery. PLoS Comput. Biol. 11(4), e1004074 (2015).Crossref, Medline, Google Scholar
- 114 . In silico predictions of 3D structures of linear and cyclic peptides with natural and non-proteinogenic residues. J. Peptide Sci. 18(1), 17–24 (2012).Crossref, Medline, CAS, Google Scholar
- 115 . Long-timescale molecular dynamics simulations of protein structure and function. Curr. Opin. Struct. Biol. 19(2), 120–127 (2009).Crossref, Medline, CAS, Google Scholar
- 116 . How fast-folding proteins fold. Science 334(6055), 517–520 (2011).Crossref, Medline, CAS, Google Scholar
- 117 . Conformational investigation of antibiotic proximicin by X-ray structure analysis and quantum studies suggest a stretched conformation of this type of gamma-peptide. Bioorg. Med. Chem. 21(12), 3582–3589 (2013).Crossref, Medline, CAS, Google Scholar
- 118 . Influence of an unnatural amino acid side chain on the conformational dynamics of peptides. ChemPhysChem 13(6), 1522–1534 (2012).Crossref, Medline, CAS, Google Scholar
- 119 . Bond distances in polypeptide backbones depend on the local conformation. Acta Crystallogr. D Biol. Crystallogr. 71(Pt 6), 1272–1283 (2015).Crossref, Medline, CAS, Google Scholar
- 120 Identification of tetrapeptides from a mixture based positional scanning library that can restore nM full agonist function of the L106P, I69T, I102S, A219V, C271Y, and C271R human melanocortin-4 polymorphic receptors (hMC4Rs). J. Med. Chem. 57(11), 4615–4628 (2014).Crossref, Medline, CAS, Google Scholar
- 121 . A dataset of experimental HLA-B*2705 peptide binding affinities. Dataset Papers in Science 2014, 4 (2014).Crossref, Google Scholar
- 122 Constrained H-Phe-Phe-NH2 analogues with high affinity to the substance P 1–7 binding site and with improved metabolic stability and cell permeability. J. Med. Chem. 56(12), 4953–4965 (2013).Crossref, Medline, CAS, Google Scholar
- 123 Backbone cyclic peptide inhibitors of protein kinase B (PKB/Akt). J. Med. Chem. 54(14), 5154–5164 (2011).Crossref, Medline, CAS, Google Scholar
- 124 Structure-based design of high affinity peptides inhibiting the interaction of p53 with MDM2 and MDMX. J. Biol. Chem. 285(3), 2174–2183 (2010).•• Describes the rational integration of phage display, biophysical experiments and structure-based design to successfully develop a peptide with dual inhibitor activities.Crossref, Medline, CAS, Google Scholar
- 125 De novo peptide design and experimental validation of histone methyltransferase inhibitors. PLoS ONE 9(4), e95535 (2014).Crossref, Medline, Google Scholar
- 126 Modulation, bioinformatic screening, and assessment of small molecular peptides targeting the vascular endothelial growth factor receptor. Cell Biochem. Biophys. 70(3), 1913–1921 (2014).Crossref, Medline, CAS, Google Scholar
- 127 . Computational design of a PDZ domain peptide inhibitor that rescues CFTR activity. PLoS Comput. Biol. 8(4), e1002477 (2012).Crossref, Medline, CAS, Google Scholar
- 128 Rational design of dual peptides targeting ghrelin and Y receptors to regulate food intake and body weight. J. Med. Chem. 58(10), 4180–4193 (2015).• Demonstrates the potential to engineer a single peptide to have multiple bioactivities.Crossref, Medline, CAS, Google Scholar
- 129 Molecular grafting onto a stable framework yields novel cyclic peptides for the treatment of multiple sclerosis. ACS Chem. Biol. 9(1), 156–163 (2014).Crossref, Medline, CAS, Google Scholar
- 130 . Toward full-sequence de novo protein design with flexible templates for human beta-defensin-2. Biophys. J. 94(2), 584–599 (2008).Crossref, Medline, CAS, Google Scholar
- 131 De novo peptide design with C3a receptor agonist and antagonist activities: theoretical predictions and experimental validation. J. Med. Chem. 55(9), 4159–4168 (2012).Crossref, Medline, CAS, Google Scholar
- 132 Derivation of ligands for the complement C3a receptor from the C-terminus of C5a. Eur. J. Pharmacol. 745, 176–181 (2014).Crossref, Medline, CAS, Google Scholar
- 133 New compstatin peptides containing N-terminal extensions and non-natural amino acids exhibit potent complement inhibition and improved solubility characteristics. J. Med. Chem. 58(2), 814–826 (2015).Crossref, Medline, CAS, Google Scholar
- 134 Discovery of entry inhibitors for HIV-1 via a new de novo protein design framework. Biophys. J. 99(10), 3445–3453 (2010).Crossref, Medline, CAS, Google Scholar
- 135 Rational design and synthesis of an orally bioavailable peptide guided by NMR amide temperature coefficients. Proc. Natl Acad. Sci. USA 111(49), 17504–17509 (2014).• Demonstrates how detailed knowledge about peptide conformation can be used to significantly improve oral bioavailability via small chemical modifications.Crossref, Medline, CAS, Google Scholar
- 136 . Cyclotides, a promising molecular scaffold for peptide-based therapeutics. Biopolymers 94(5), 611–616 (2010).Crossref, Medline, CAS, Google Scholar
- 137 . Cyclotides as grafting frameworks for protein engineering and drug design applications. Biopolymers 100(5), 480–491 (2013).Crossref, Medline, CAS, Google Scholar
- 138 Orally active peptidic bradykinin B1 receptor antagonists engineered from a cyclotide scaffold for inflammatory pain treatment. Angew. Chem. Int. Ed. Engl. 51(23), 5620–5624 (2012).Crossref, Medline, CAS, Google Scholar

