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Methods for calculating geometry and molecular energy: Molecular Mechanics. Quantomechanical methods (semi-empirical and ab initio, DFT methods). Mixed Quantum Mechanics / Molecular Mechanics methods for the study of large molecular and supramolecular systems. Use of electron density and electrostatic potential (MEP) for the study of similarity and for molecular recognition. Molecular simulation methods: Introduction to the problem of simulating molecules of chemical-biological interest. Molecular dynamics: coarse grained and atomistic methods. Solvation methods. Some examples: solvation of amino acids and study of a protein in solution. Conformational analysis for molecules of biological interest: Systematic methods and statistical methods (Monte Carlo). The problem of conformational analysis for systems with a high number of degrees of freedom. Applications of the methods: Modeling of molecules of biological interest - introduction to drug design: computational methods applied to biomolecules: Determination of the 3D structure of peptides and proteins (ab initio methods, Homology modeling and folding recognition). Applications to modeling and design of peptidomimetics. The design of a drug. Molecular similarity. Oligonucleotides and single and double strand nucleic acids and the hydrogen bridge bond. Simulations of peptides and proteins in lipid bilayers: state of the art and application examples. Bibliographic research and how to solve a case study.

Review of basic concepts on the structure, organization and functioning of the human genome. The Ensembl database, description and operation. Structure of a human gene in Ensembl, sequence information retrieval, protein structure, functional and clinical annotations. The UCSC browser genome, description and operation. UCSC structure and annotation of a human gene, retrieval of functional and expression information. Introduction to NGS Sequencing. Illumina sequencing methodology. Introduction to RNA-seq methodology. Design of an RNA-seq experiment and related bioinformatics data analysis. Introduction to systems biology and network theory. Examples of networks in biology and genomics. Pharmacogenomics. Protein-protein and protein-drug interaction databases. Basic usage of the Cytoscape software and the R statistical programming language. Examples of research articles available on Pubmed discussing topics related to arguments related to the course.

Introduction to the course. Performance indices of an analytical method (LOD, LOQ, accuracy and precision, accuracy, repeatability, reproducibility, recovery, dynamic and linear range, robustness etc.). Basic principles of instrumentation for liquid and gas chromatography. Introduction to omic techniques. Use of chromatographic techniques (HPLC and GC) and their coupling with mass spectrometry in the omic sciences. Targeted and untargeted proteomics. Targeted and untargeted metabolomics. Notes on methods of pre-treatment of the sample in the omic field. Notes on data treatment in the omic field. Strategies for identifying the best analytical approach to solving a given problem. Bibliographic research and how to solve a case study.

Radiation-matter interaction Electronic spectroscopies (absorption and photoluminescence, stationary, resolved over time and anisotropy) both on liquids and on solids (outline of nanotechnological and biotechnological formulations and additives) Vibrational spectroscopies (IR and Raman) Circular dichroism Study of the solid / liquid, solid / gas and liquid / liquid interfaces. Definition of dispersed systems and colloidal systems. Classification based on the size of the dispersed particles and surface tension. Optical, electrical and kinetic properties of colloidal systems and their stability. Techniques for studying particle sizes in dispersed systems: Dynamic Light Scattering (DLS), optical microscopy and transmission electron microscopy (TEM) and scanning electron microscopy (SEM). Surfactants and liposomes and their chemical-physical properties. Nanomaterials and nanoparticles for biotechnological and biomedical applications. Examples of applications of nanoparticles in medicine: drug delivery and theranostic.

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Basic principles of protein science: -Amino acids and proteins: chemical and structural properties -Peptide bond and protein structure -Proteins as information molecules: sequence and database analysis Structural analysis techniques: Structural biology: spectroscopic and diffrattometric techniques for structural protein investigation Protein visualization programs Structural protein prediction Molecular modelling "Case studies" and application implications of Protein Science: -Protein science and drug design: principles, examples and discussion of scientific publications -Protein Sciences and Protein Engineering: Principles, Examples and discussion of scientific publications PROTEIN ENGINEERING - Introduction to the production of recombinant proteins - Cloning techniques and expression vectors - Site-directed and random mutagenesis - Chimeric proteins - Rational protein design: theoretical principles and experimental methods - Selection and evaluation of protein variants: biochemical assays and desired property analysis. CHEMICAL-PHYSICAL METHODS FOR PROTEIN ANALYSIS: -Chromatographic techniques for protein purification - Salting in/out. - Methods for assessing the concentration and purity of proteins. Methods for assessing protein stability and folding: - Differential scanning fluormetry and differential scanning calorimetry - Circular dicroism - "Light-Scattering" for the study of the quaternary structure of proteins -Methods for the analysis of protein-protein and protein-ligand interactions: - Isothermal titration calorimetry - Surface plasmon resonance - Microscale thermophoresis

Methods of Nuclear Magnetic Resonance Spectroscopy to study structure and interactions of biomolecules. - Basic principles of the technique; nuclei in a magnetic field; population of nuclear spin energy levels; Larmor precession frequency. Pulse NMR method: pulse angle, rotating coordinate system, Bloch equations, relaxation, Fourier transform; - NMR parameters: chemical shift, scalar coupling, dipolar coupling. Theoretical aspects and applications through exercises of spectral interpretation for the structural characterization of small molecules; - Multidimensional NMR techniques for the structural determination of peptide and proteins: 1) sequence specific assignment of protein resonances; 2) NOE: principles and applications for the acquisition of structural constraints; 3) Basic concepts of computational methods to obtain 3D protein structures. - NMR screening in drug discovery: characterization of protein-ligand and protein-protein interactions. 1) Techniques based on the observation of the binder signals (Water-Logsy and Saturation Transfer Difference); 2) Methods based on the observation of protein signals (Chemical Shift Perturbation Mapping).

Module 1 (1CFU): intellectual property. Intellectual property rights: general information about utility model, industrial design, trademark, copyright. Patent and patentability. Claims and description. Patent convention and protection strategy. Prior art search and freedom to operate. Module 2 (1 CFU): regulatory affairs. Introduction to the role of the regulatory affairs professional. Medicines regulation and main international guidelines. Types of drug registration (national and European). The role of regulatory agencies, their organization, and involvement in the development, registration, market launch and maintenance of the AIC. Module 3 (2 CFU): pharmacoeconomics and market access. Introduction to pharmacoeconomic analyses. Health Technology Assessment (HTA), Market Access (MA), Price & Reimbursement (P&R) in the main European countries. Managed Entry Agreements (MEAs). Regional and local policies. Focus on orphan drugs, advanced/ personalized therapies, neglected tropical diseases and drug access in developing countries.

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Bioelectric phenomena. Processes of transport across the plasma membrane. Biophysical structure and properties of ion channels. Steady state properties of the membrane. Conduction properties of cells. Membrane excitability. Ionic channels, membrane potential and cell cycle. Ionic channels as drugs targets. Channelopathies. Techniques used to investigate bioelectric phenomena and applications in drug screening and development field. The calcium ion as the second messenger. Intracellular calcium homeostasis. Calcium signaling toolkit as a pharmacological target. Techniques and probes for measuring the dynamics and concentrations of calcium in the various intracellular compartments. Use of calcium sensors in drug development and screening technologies. The cells of the nervous system. Homeostatic role of glial cells. Glia-neuron interaction and its alterations in neurological and neurodegenerative diseases. Applications for the development of diagnostic, preventive and therapeutic strategies

Receptors with intrinsic enzymatic activity, receptors coupled with cytosolic proteins, G coupled receptors, nuclear receptors, enzymes. Targeted cancer therapies: action on cell proliferation, angiogenesis and apoptosis. Selection of patients who can benefit from molecular target therapies.

Mechanisms underlying immune tolerance and pathological basis of autoimmune diseases. Type I, II, III and IV hypersensitivity reactions. Pathogenesis, current therapeutic options and new potential targets for the main immune-mediated diseases affecting the skin (psoriasis, alopecia, vitiligo, atopic dermatitis), the gastrointestinal system (inflammatory bowel disease, celiac disease), the joints (rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis) and for those with systemic involvement (Systemic Lupus Erythematosus)

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Main clinical and diagnostic applications of biotechnological drugs. Pharmacodynamic, pharmacokinetic, tolerability profile, adverse events of biotech drugs with examples from different therapeutic areas. Examples of molecular engineering approaches to improve pharmacokinetic and / or pharmacodynamic and/or immunogenicity of relevant biotech drugs. Discussion of selected examples of discovery and development of therapeutic proteins, Mabs, DNA/RNA based drugs and vaccines.

Amino acids. Amino acids chirality. Acid and basic properties of amino acids. How to react amino acids? Peptides secondary structures. Natural peptides. Peptides as drugs. Orally available peptides. Peptides thermically stable. Chemical synthesis of peptides. Protecting groups of peptides. Coupling methods. The problem of racemization. Chemical ligation. Solid phase of peptides. Combinatorial chemistry of peptides. Purification of peptides. How to improve the druglikeness of a peptide. Pseudopetides. Peptidomimetics.

The following units from the textbook “Cambridge English for Scientists” will be covered during the lessons : Unit 1 – Getting started in research Unit 2 – The scientific community Unit 3 – Finding a direction for your research Unit 4 – Designing an experiment Unit 5 – Describing an experiment Unit 6 – Writing up research 1: materials and methods Unit 7 – Writing up research 2: presenting data Unit 8 – Writing up research 3: results and discussion Unit 9 – Writing up research 4: introduction and abstract Unit 10 – Presenting research at a conference With regard to the listening exercises, the audios are available on the CD included in the book. In addition, the book includes transcripts of the audios and keys of the exercises.

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- Introduction to the pharmacology of ATMPs - Cell therapy - Gene therapy - CAR-T and oncologic diseases - Engineered tissue therapy - Regulatory aspects and procedures of ATMPs

Stem cells, cellular reprogramming and use of these cells in cell therapy protocols in preclinical and potential applications in the clinic. Isolation, in vitro expansion and preparation of cells for experimental cell therapy. Vectors used for gene transfer: viral vectors and non-viral. Origin, construction and modi�cation. Modulation of Expression cassettes: Constitutive and regulated expression. transcriptional or post-transcriptional expression regulation Immune response to vectors and transgenes used in gene transfer. Concepts of ex vivo and in vivo gene therapy. Clinical trials using cell and gene therapy strategies of target diseases. use of animal models to study genetic diseases

1) Guided tissue regeneration: scaffolds, growth factors, active molecules. 2) Cell culture techniques in monolayer and 3D on scaffolds: how cellular behaviours is modified and which different analysis techniques has to be used (stereomicroscopy, SEM confocal optical fluorescence microscopy; biochemical and molecular techniques, citotoxicity, cell migration, adhesion and proliferation on scaffolds) 3) Techniques for studying tissue regeneration (macroscopic, mechanical, microscopic, biochemical, molecular) and experimental examples with seminars on laboratory experiences in bone and cartilage regeneration

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• Pharmaceutical aspects of biotherapeutics: therapeutic proteins, monoclonal antibodies (mAb), antibody-drug conjugates (ADC), other types of conjugates. • Post translational modifications: glycosylation profiles and analytical strategies for their determination. • Chemical degradation of therapeutic proteins, examples of the reactions involved. • Quality control of biotherapeutics: definition of quality, implementation of a quality assurance system, identification of the critical quality attributes (CQAs) of biotherapeutics. ICH guidelines: stability (ICH Q5C), specification (ICH QB6), comparability (ICH QE5). • Fundamentals of the most common analytical techniques employed in the characterization and quality control of biotherapeutics. Examples of applications. Separative techniques: HPLC (SEC, HILIC, IEX, HIC, AC), capillary electrophoresis CE (CZE, MEKC, CIEF). Detectors: UV-Vis, FL, MS. Ion sources: ESI, MALDI, triple qualdrupole (QQQ) and operative modes in tandem analysis, qTOF, Orbitrap, ion traps. Analytical approaches based on mass spectrometry operative modes.

Definition and classification of pharmaceutical and food biotechnologies. Microorganisms as cell factory: characteristics and selection of best performing biological system. Starter cultures, probiotics; classification of fermentations. Bioreactors for pharma and food applications. Media preparation; bacterial kinetics. Downstream processing; purification, isolation, concentration and formulation.: case studies. Production of sustainable biomasses. Industrial microbiology and bio-products: alcohols, organic acids, amino acids, carbohydrates, prebiotic oligosaccharides, lipids, bioactive peptides, vitamins, antibiotics, secondary metabolites, colours and pigments, flavours). Enzymes (free phase and immobilized); examples of applications. Recombinant biotechnologies; GMMO’s, GMO’s. Analytical biotechnologies and novel molecular approaches (probes; novel techniques of analysis, micro- and nano-based sensors for food safety and detection of contaminants/residues).

Introduction to the fundamental bioconjugation approaches, what types of bioconjugates exist (i. e. antibody-drug, protein-small molecule, imaging probe-protein or nanoparticle, etc) and their uses. Definition of functional groups suitable for the conjugation of bifunctional chelating agents or drugs to biomolecules (peptides, proteins, polysaccharides, polynucleotides) or protein vectors to nanoparticles. Analysis of the conjugation approaches through the formation of a stable bioconjugate and / or capable of releasing a bioactive product or the probe. Use of homo- and hetero-bifunctional linkers, cleavable and non-cleavable for bioconjugation. Analysis of the probes that can be used for bioconjugation. New organic synthetic strategies for bioconjugation: 1) use of Click Chemistry reactions for bioconjugation: Huisgen's 1,3-dipolar cycloaddition, Staudinger Ligation, Inverse Electronic Demand Diels-Alder reaction; 2) native chemical ligation; 3) site-specific labeling techniques to deliver proteins to the site of interest; 4) bioorthogonal reactions and in vivo bioconjugation.

1. Physical principles of imaging techniques: basics of atomic and nuclear structure, elementary particles, electromagnetism, waves. 2. Introduction to imaging techniques: computed tomography (CT), positron emission tomography (PET), single-photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), optical imaging (OI), ultrasound (US) and photoacoustic imaging. Basics of combined imaging techniques. 3. Molecular Imaging: definition and purposes. Molecular Imaging probes for PET, SPECT, MRI, OI, US. Bimodal molecular imaging probes.

• Medicinal products: definitions and background. Marketing Authorization. • Pharmaceutical dosage forms (PDF): definition of dosage form; principles of biopharmaceutics (drug delivery, absorption, distribution, metabolization and elimination; concept of bioavailability); route of drug administration (oral sublingual, buccal, rectal, transdermal, nasal, pulmonary, parenteral, topical, ophtalmic, vaginal route); concept of preformulation. • Pharmaceutical powders: definition; powder properties. Powders as drug dosage forms • Materials employed in pharmaceutical field. Measure, control and regulation of temperature, pressure and flow. Ventilated, controlled climate and clean rooms. • Processes for solid dosage forms: milling, seiving, granulation, desiccation. • Granules: formulation of granules; introduction to granulation, granulation methods (wet granulation and dry granulation) and granulation mechanisms. • Tablets: definition; characteristics; classification; excipients for tablets (fillers, binders, lubricants, antiadherents, glidants, disintegrants, colourants, flavours, modified release agents); examples of tablet formulations; specific technological tests; coating of tablets (sugar coating, film coating, press coating). • Capsules: definition; hard gelatin capsules: excipients, shell manufacturing procedure and capsule filling; soft gelatin capsules; production and specific technological tests on hard and soft capsules. • Multiunit drug delivery systems: micro- and nano-systems. Development, manufacturing and quality control. • Solutions: properties of solutions; surfactants, interfacial tension, HLB; pharmaceutical solutions and excipients; aqueous and non-aqueous solutions. Water for pharmaceutical and biotechnological uses: production, storage and distribution. • Parenteral dosage forms: classification; requirements; vehicles; packaging. Small volume preparations (SVP) and large volume preparations (LVP); parenteral nutrition. Manufacturing of parenteral medicines. Powders for parenteral administration: Freeze Drying. Sterilization: definition, physical and chemical methods; sterility assurance level. • Biological/biotechnological drugs: routes of administration of peptide drugs, biopharmaceutical and pharmacokinetic considerations. Antigenicity and immunogenicity. Preformulation studies, formulation and stability aspects of biotechnological products. The PEGylation of peptides and proteins. Stages in the manufacturing process and quality testing of biological/biotechnological medicinal products. Pharmaceutical aspects for the production of vaccines. • Advanced Therapy Medicinal Products (ATMP): Introductory concepts related to Advanced Therapy Products and Regenerative Medicine. Regulatory framework. Large-scale and hospital-based production of medicinal products for gene therapy, somatic cell therapy and advanced combination therapies.

Microbiology in the Biopharmaceutical Field module:• Bioprospecting: exploration of microbial biodiversity for biotechnological purposes • Industrial use of microorganisms • Isolation and selection of microorganisms of pharmaceutical interest • Microorganisms of biotechnological and biopharmaceutical interest: E. coli - Streptomyces - Bacillus - Yeasts - Filamentous fungi • Methods of microbial cultivation • Evaluation of microbial development in industrial processes • Introduction to procedures for obtaining microbial metabolites, measurements, regulation, and technologies in fermentation processes • Improvement of production processes • Overview of methods for recovering biotechnological products • Molecular basis of production processes: some examples - Primary metabolites - Antibiotics - Vitamins - Recombinant proteins. Industrial Biotechnologies module: Biotransformations: definitions and characteristics. Comparison between chemical synthesis and biocatalyzed reactions. Enzyme structure, functions, mechanisms, and scope in organic synthesis. Specificity, selectivity of enzymes and methods for the study of enzymatic properties. Main classes of enzymes used in organic synthesis and in the chemical industry: Oxidoreductases -Transferases -Hydrolases -Lyases -Isomerases -Ligases Biotransformations to produce products of pharmaceutical relevance: examples of industrial processes. Bioreactors module: From 2D static culture to 3D dynamic culture (1h) • Definition of devices for dynamic culture of microrganisms/cells/tissues (bioreactors) and advantages for basic research and large-scale industrial production (2h) • Bioreactor types and purposes in tissue engineering field (3h) • Bioreactor subsystems (3h) • Cell expansion bioreactors (2h) • Tissue maturation bioreactors (3h) • In vitro model system for drug screening and disease modeling / Microfluidic bioreactors (2h)

• Bioprospection: exploration of microbial biodiversity for biotechnological purposes (definition and examples). • The industrial use of microorganisms: history and applications in the pharmaceutical field • Isolation and selection of microorganisms of biopharmaceutical interest (screening approach and examples) • Microorganisms of biotechnological and biopharmaceutical interest: characteristics and applications - E. coli - Streptomyces - Bacillus - Yeasts - Filamentous mushrooms • Methods for cultivation of microorganisms (kinetic aspects of microbiological processes, in-batch growth curve, continuous fermentation and fed-batch fermentation) • Evaluation of microbial development in industrial processes (microbial cultures analysis, direct methods, indirect methods) • Procedures for obtaining microbial metabolites, measurements, regulation and technologies in fermentation processes (bioreactors and the fermentation process) • The improvement of production processes (improvement of strains and culture media, raw materials for microbial growth used in the industrial field) • Overview of recovery methods for biotechnological products - downstream (clarification, cell disintegration, precipitation, membrane processes, extraction, evaporation, distillation, final treatments) • The molecular basis of production processes: some examples - Primary metabolites (amino acids) - Antibiotics - Vitamins - Microorganisms for the production of recombinant proteins (insulin, surface antigen of the hepatitis B virus)

From 2D static culture to 3D dynamic culture (1h) Definition of devices for dynamic culture of microrganisms/cells/tissues (bioreactors) and advantages for basic research and large-scale industrial production (2h) Bioreactor types and purposes in tissue engineering field (3h) Bioreactor subsystems (3h) Cell expansion bioreactors (2h) Tissue maturation bioreactors (3h) In vitro model system for drug screening and disease modeling / Microfluidic bioreactors (2h)

Biotransformations: definitions and characteristics. Comparison between chemical synthesis and biocatalyzed reactions. Enzyme structure, functions, mechanisms, and scope in organic synthesis. Specificity, selectivity of enzymes and methods for the study of enzymatic properties. Main classes of enzymes used in organic synthesis and in the chemical industry: Oxidoreductases -Transferases -Hydrolases -Lyases -Isomerases -Ligases Biotransformations to produce products of pharmaceutical relevance: examples of industrial processes.

R software. Elementary operations. Functions and graphs. Import, export in R. Data Structures, packages. Matrices, lists, arrays. The data frame. Working with sata: selecting elements, logical operators. Loops and conditionals. Missing data. Additional graphics packages: ggplot2. Regression line and regression curves. Anova. Pharmacokinetic models. Clustering. Simulations.