Peptide Drug Discovery and Development

Miguel Castanho is head of the Biochemistry department of the School of Medicine at the University of Lisbon (Portugal). He also leads the Physical Biochemistry research unit at the Institute of Molecular Medicine. His main field of research is the interaction of peptide drugs with lipids, in particular the role of lipid membranes in the mechanism of action of peptide drugs. Nuno C. Santos is the leader of the Biomembranes Unit of the Institute of Molecular Medicine. His research is centered on the specific functions of biological membranes lipids and proteins, with a special focus on their relevance for pathologic processes ranging from viral or bacterial infection to cardiovascular diseases. Together, Miguel Castanho and Nuno C. Santos have been involved in many collaborative drug discovery and development projects with industry partners in Europe, USA, Canada, and China.

“This book illustrates many of the technical prerequisites and describes model systems in which these objectives have been at least partially achieved.   It convincingly shows that peptide-based drug discovery has become a mainstream activity in the drug discovery and development process.”  (ChemMedChem, 2012)

• Preface PART I: The Academia -Market Bouncing of Peptide Drugs -Challenges and Strategies in Translational Research with Peptide Drugs PEPTIDES AS LEADS FOR DRUG DISCOVERYIntroductionOverview of Process for Transforming Peptides to PeptidomimeticsHCMV ProteaseHCV ProteaseHerpes Simplex VirusReninHIVConclusions MARKETING ANTIMICROBIAL PEPTIDES: A CRITICAL ACADEMIC POINT OF VIEWIntroductionBasic Research: Antimicrobial PeptidesPatentsPotential Applications of AMPsTechnology Transfer: Valorization, Licensing, or Spin-Off CreationSpin-Off Creation: An Academic Point of View ORAL PEPTIDE DRUG DELIVERY: STRATEGIES TO OVERCOME CHALLENGESIntroductionChallenges Associated with Oral Petide DeliveryStrategies to Overcome the Barriers of the Gastrointestinal TractConclusions RATIONAL DESIGN OF AMPHIPATHIC ALPHA-HELICAL AND CYCLIC BETA-SHEET ANTIMICROBIAL PEPTIDES: SPECIFICITY AND THERAPEUTIC POTENTIALIntroduction to Antimicrobial PeptidesAntimicrobial and Hemolytic Activities of Amphipathic Alpha-Helical Antimicrobial Peptides: Mechanisms and SelectivityStructure-Activity Relationship Studies of Amphipathic Alpha-Helical and Cyclic Beta-Sheet Antimicrobial Peptides: Optimization of Pathogen Selectivity and Prevention of Host ToxicityCommercialization of Antimicrobial PeptidesTherapeutic Potential CONOTOXIN-BASED LEADS IN DRUG DESIGNIntroductionConotoxin Classification and TargetsConotoxins as Drug LeadsConclusions PLANT ANTIMICROBIAL PEPTIDES: FROM BASIC STRUCTURES TO APPLIED RESEARCHIntroductionThe Diversity of Plant Antimicrobial Peptides: Focusing on Tissue Localization and Plant Species DistributionPossible Structural Folds Found in Plant AMPs to DateNew Biotechnological Products Produced from Plant Peptides PART II: Peptide Drugs' Translational Tales -Peptide Drugs Before, Through and After Industry Pipelines OMIGANAN PENTAHYDOCHLORIDE: A NOVEL, BROAD-SPECTRUM ANTIMICROBIAL PEPTIDE FOR TOPICAL USEOmiganan: A Novel Anti-Infective Agent for Topical IndicationsStructure and Mechanism of ActionSpectrum of ActivityPreclinical Efficacy StudiesPreclinical Toxicology StudiesClinical StudiesConclusions TURNING ENDOGENOUS PEPTIDES INTO NEW ANALGESICS: THE EXAMPLE OF KYOTORPHIN DERIVATIVESIntroductionPeptides as Future Drug CandidatesCentral Nervous System Anagesic PeptidesEndogeneous Opioid SystemsStrategies to Deliver Analgesic Peptides to the BrainDevelopment of New Opioid-Derived PeptidesKyotorphin -The Potential of an Endogenous DipeptideNew KTP DerivativesAssessing BBB Permeability with Peptide -Membrane Partition StudiesKyotorphines: Partition to the Membrane and Enhanced Analgesic ActivityAcademia and Pharmaceutical Industry: Friends or Foes? THE DEVELOPMENT OF ROMIPLOSTIM -A THERAPEUTIC PEPTIBODY USED TO STIMLATE PLATELET PRODUCTIONIntroductionThrombopoietin and c-MplDiscovery and Optimization of RomiplostimPharmacodynamics (PD) and Pharmacokinetics (PK) of RomiplostimA Brief ITP PrimerRomiplostim Clinical DataSafety and Other Insights Gained from Romiplostim Design and Development HIV VS HIV: TURNING HIV-DERIVED PEPTIDES INTO DRUGSIntroductionHIV-1 Envelope ProteinHIV Entry and Its InhibitionHIV-1 Fusion Inhibitors: From Bench to Clinical AdministrationNew Strategies for Creating New HIV Fusion Inhibitor PeptidesDrug-Resistance and Combination TherapyConcluding Remarks SIFUVIRTIDE, A NOVEL HIV-1 FUSION INHIBITORIdeal Drug Target HIV-1 pg41Structure-Based Drug Design of SifuvirtideHigh Potency of SifuvirtideLimited Drug ResistanceEnhancement of the Efficiency of Sifuvirtide by Biomembrane SelectivityPharmacokinetics of Sifuvirtide with Long Half-LifeStratification of Monotherapy20 mg Sifuvirtide Once Daily vs. 100 mg T10 Twice DailyConclusions and Discussion PART III: Whither Peptide Drugs? Peptides Shaping the Future of Drug Development ENDOGENOUS PEPTIDES AND THEIR RECEPTORS AS DRUG DISCOVERY TARGETS FOR THE TREATMENT OF METABOLIC DISEASECentrally Secreted Neuropeptide SystemsPeripherally Secreted NeuropeptidesSummary TRANSLATION OF MOTILIN AND GHRELIN RECEPTOR AGONISTS INTO DRUGS FOR GASTROINTESTINAL DISORDERSIntroductionMotilin and Ghrelin Receptor Agonists Under DevelopmentTranslational Value of Preclinical AssaysClinical Translation: Selecting the "Right" Patient PopulationClinical Development of Motilin and Ghrelin Receptor AgonistsConclusions OF MICE AND MEN: TRANSLATIONAL RESEARCH ON AMYLIN AGONISMOverview of Amylin PhysiologyPramlintide: An Amylin AgonistAmylin Agonism: Translational Research in Insulin-Dependent DiabetesAmylin Agonism: Translational Research in Obesity PEPTIDES AND POLYPEPTIDES AS IMMUNOMODULATORS AND THEIR CONSEQUENTIAL THERAPEUTIC EFFECT IN MULTIPLE SCLEROSIS AND OTHER AUTOIMMUNE DISEASESIntroductionPeptides as Antigens and VaccinesPeptides as ImmunomodulatorsDevelopment of Copolymer 1 -A Polypeptide Immunomodulator Drug for the Treatment of Multiple SclerosisAdditional Immunomodulatory Peptides as Drug CandidatesSummary and Concluding Remarks DEVELOPMENT OF ANTIBODY FRAGMETNS FOR THERAPEUTIC APPLICATIONSAntibodiesConclusions