Biopharmaceuticals: Design and Modification of Biomacromolecules

Besides an introduction to the concepts and methods that are relevant for investigating and understanding the physicochemical and pharmacological properties of macromolecules, the course focuses on the design, discovery, and applicability of biopharmaceutical drugs, primarily those based on peptides or proteins.

Furthermore, this course will form the basis for studies on optimization of pharmaceutical properties of peptides, proteins, and nucleic acids in relation to preclinial and clinical drug development. Finally, drug leads derived from these classes of macromolecules (e.g., peptidomimetics) will be discussed.

These subjects will be introduced via lectures (based on comprehensive reviews and primary research articles), while the class sessions will comprise student presentations and discussion of selected scientific articles in order to facilitate an in-depth understanding of both theoretical and practical aspects of biopharmaceutical drug research. In addition, some class sessions will comprise theoretical execises on the basic elements of the course (e.g. peptide synthesis and protein modification). Also, the course comprises practical exercises in peptide synthesis and biochemical assay performance in the laboratory. These exercises illustrate basic solid-phase peptide synthesis (SPPS) methodology and biochemical evaluation of enzyme activity. For each excercise a laboratory notebook should be kept in order to facilitate writing a mandatory group report, which also includes interpretation and discussion of the achieved results (Yield, LC-MS analysis, and Michaels-Menten parameters).

The most relevant compound classes and their applications are briefly outlined below:

• Peptide- and protein-based drugs, inculding modified peptide and proteins (primary content of the course).
• Introduction to antibodies and therapeutic relevance.
• Introduction to oligonucleotides for gene therapy and antisense siRNA as putative biopharmaceutical drugs.
• Introduction to vaccines.

Methods and concepts:

• Importance of structure for pharmacological activity and suitable drug properties: charge, solubility, stability and delivery. 
• Primary sequence and folding into secondary and tertiary structures and methods for manipulating these.
• Principles of solid-phase peptide synthesis (incl. combinatorial and parallel approaches) and optimization. Advanced peptide chemistry including selection of linkers, coupling reagents and protecting groups.
• Protein biosynthesis and modification: post-translational and chemical transformations.
• Genetic and protein engineering as a discovery and production tool for biological protein and peptide expression and modification.
• Practical manual solid-phase peptide synthesis and simple modification of proteins.
• Chemical protein synthesis and semisynthesis