Biopharmaceuticals: Design and Modification of Biomacromolecules

Course content

Besides an introduction to the concepts and methods that are relevant for investigating and understanding the physicochemical and pharmacological properties of macromolecules, the course focus 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, oligonucleotide analogues and oligosaccharides) as well as relevant delivery vehicles will be discussed.
These subjects will be introduced via lectures (based on book chapters and comprehensive reviews and 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 a chemical synthesis lab. These exercises illustrates basic solid-phase peptide synthesis methodology and protein modification. For each excercise a laboratory notebook should be kept in order to facilitate writing of mandatory reports which also comprise answering specific questions and interpretation of analytical results (LC-MS, MALDI and ELISA).


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).
  • Delivery vehicles for biopharmaceuticals.
  • Oligonucleotides for gene therapy and antisense siRNA as putative biopharmaceutical drugs.
  • Introduction to antibodies and vaccines.



Methods and concepts:

  • Importance of structure for pharmacological activity and suitable drug properties: charge, solubility and stability, primary sequence and folding into secondary and tertiary structures.
  • 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
Education

MSc in Medicinal Chemistry - compulsory

Cand.pharm. - elective

Cand.scient.pharm. - elective

MSc in Pharmaceutical Science - elective

 

Learning outcome

The purpose of this course is to provide students with theoretical knowledge on biopharmaceutical drug discovery as a central part of contemporary and future interdisciplinary drug discovery efforts in academia as well as in the biotech and pharmaceutical industry. The focus will primarily be on peptides and proteins as they currently constitute the most important class of biopharmaceuticals.
An additional aim is to introduce students to methodologies related to chemical synthesis, biological expression, and modification of biopharmaceuticals with a focus on their applications in drug discovery and development.

 

At the end of the course, students are expected to have gained:

Knowledge

  • At the end of the course the student has gained comprehension of the steps involved in biopharmaceutical drug discovery
  • Understanding of aspects of chemical peptide synthesis relevant for biopharmaceutical drug discovery
  • Understanding of post-translational peptide/protein modifications
  • Understanding of methods used in chemical protein modification
  • Understanding of the concept of unnatural mutagenesis
  • Basic appreciation of the potential of novel types of biopharmaceuticals (e.g. nucleic acids and analogs thereof) in sufficient detail to follow future scientific developments

 

Skills

  • Capability to assess the implications of peptide/protein sequence on their folding into secondary/tertiary structure
  • Capability to search and read relevant literature and use this knowledge in biopharmaceutical research projects.
  • Capability to perform simple solid-phase peptide synthesis and protein modification

 

Competences

  • The student will be able to read and discuss research examples concerning optimization of biologically active peptide drug leads with respect to pharmacological properties including bioavailability and in vitro cytotoxicity
  • The student will be able to apply basic theory of peptide optimization and protein engineering/​expression related to practical development of biopharmaceuticals

 

Lectures: 21
Class sessions: 12
Writing of individual study report (preferably 40 hours during last 3 weeks)
Practical exercises (15 hours in lab)

Peptide Synthesis and Applications, K. J. Jensen, A. P. Tofteng, S. L. Pedersen (Eds), Springer Protocols, Humana Press, 2013.

Selected book chapters:

Textbook of Drug Design and Discovery (CRC Press; eds. P. Krogsgaard-Larsen K. Strømgaard, U. Madsen)

Pharmaceutical Formulation Development of Peptides and Proteins (CRC Press 2012; eds. L. Hovgaard, S. Frøkjær, M. van de Weert) 

Peptide and protein derivatives (p. 131-148), in Pharmaceutical Formulation Development of Peptides and Proteins (Taylor & Francis 2012; eds. M. van de Weert, S. Frøkjær & L. Hovgaard)
 

Supplementary reviews and research papers covering the following topics:

Examples of subclasses of potential drug leads (peptides, peptidomimetics and proteins), known biopharmaceuticals (e.g. peptide hormones, cytokines, antibodies, nucleic acids and analogues thereof, as well as adjuvants/vaccines and drug delivery vehicles.

All teaching materials besides the textbook comprise parts of textbooks already used in other courses concerning biopharmaceuticals, or it will be available via the course homepage or as handout material.

Basic knowledge in organic and bioorganic chemistry and molecular biology is a prerequisite.

ECTS
See exam description
Type of assessment
Course participation
Course certificate: The students work in groups of 3-4 persons preparing a joint lab journal on the performed experiments and answering the associated questions.
Aid
All aids allowed

The lab teachers may be approached for guidance in answering the associated questions.

Marking scale
passed/not passed
Censorship form
No external censorship
Criteria for exam assessment

 

To obtain a course certificate the student must be able to:

Knowledge:

  • show that the basic concepts have been understood through answering  the associated questions.
  • show that the basic concepts have been understood.
  • A theoretical background to understand synthesis descriptions of simple chemical reactions involving peptides relevant as biopharmaceuticals.

Skills:

  • carry out the laboratory work to satisfaction.
  • perform experiments with acceptable results and described in a scientific way, so that the synthesis and analysis excercises may be repeated.
  • performing simple syntheses and analysis of peptides.

Competences:

  • write a report in a scientific language how exsperimental work has been performed.
ECTS
See exam description
Type of assessment
Written assignment
Individual written assignment (essay) in the format of a scientific minireview (size: min 15.000 and max. 25.000 characters including spaces; supporting figures allowed) based on literature studies on a subject agreed upon with one of the teachers and approved with the course directors. The essay must relate to a substantial content of chemistry as well as a biology/​​biopharmaceutical aspect. The student will have 3 weeks to prepare this.
Aid
All aids allowed
Marking scale
7-point grading scale
Censorship form
No external censorship
Criteria for exam assessment


To achieve the grade 12 the student must be able to:

Knowledge

  • Comprehend the steps involved in biopharmaceutical drug discovery
  • Understand of aspects of chemical peptide synthesis relevant for biopharmaceutical drug discovery
  • Understand of post-translational peptide/protein modifications
  • Understand of methods used in chemical protein modification
  • Understand of the concept of unnatural mutagenesis
  • Appreciate the potential of novel types of biopharmaceuticals comprising nucleic acids (and analogs thereof) and oligosaccharides in sufficient detail to follow future scientific developments in these fields

 

Skills

  • Assess the implications of peptide/protein sequence on their folding into secondary/tertiary structure
  • Device chemical synthesis of relevant peptides and modification of protein drugs 
  • Search and read relevant literature and use this knowledge in biopharmaceutical research projects.
  • Discuss and illustrate how a specific type of biopharmaceuticals may be discovered via synthesis/expression of leads that undergo optimization using appropriate methodologies.

 

Competences

  • The student will be able to read and discuss research examples concerning optimization of biologically active peptide drug leads with respect to pharmacological properties including bioavailability and in vitro cytotoxicity
  • The student will be able to apply basic theory of peptide optimization and protein engineering/​​expression related to practical development of biopharmaceuticals
ECTS
See exam description
Type of assessment
Written examination, 1 hour under invigilation
Multiple-choice test with 25-35 statements.
Aid

No aids are allowed

Refer to the IT exams homepage link where the standard programs and IT tools available for the students’ disposal during IT exams under The Faculty of Health and Medical Sciences are listed.

USB-stick is not allowed.

Marking scale
7-point grading scale
Censorship form
No external censorship
Criteria for exam assessment

To achieve the grade 12 the student must be able to:

Knowledge

  • Comprehend the steps involved in chemical peptide synthesis
  • Understanding properties and utility of specific commonly used reagents, building blocks and protecting groups involved in chemical peptide synthesis
  • Understand post-translational peptide/protein modifications including reagents and methods
  • Understand methods and specific common reagents used in chemical protein modification
  • Understand the concept and specific methods involved in unnatural mutagenesis
  • Understand basic concepts related to peptide optimization
  • Understand basic properties of peptidomimetics and biologically active peptides (e.g. AMPs and CPPs) 
  • Comprehend basic concepts, methods and properties related to nucleic acids (and analogs thereof), antibodies, and vaccines 

 

Skills

  • Assess utility and application of specific common reagents and methods related to chemical peptide synthesis
  • Assess utility and application of specific common reagents and methods related to modification of proteins
  • Assess concepts and specific methods involved in peptide optimization
  • Assess the properties of peptidomimetics and specific types of biologically active peptides (e.g. AMPs and CPPs)
  • Assess basic concepts, methods and properties related to nucleic acids (and analogs thereof), antibodies, and vaccines  

 

Competences

  • Understand examples concerning biologically active peptide/protein drug leads with respect to chemical synthesis/modification and optimization 
  • Apply basic theory of peptide synthesis and optimization and protein engineering/​​expression related to practical development of biopharmaceuticals
  • Category
  • Hours
  • Lectures
  • 21
  • Colloquia
  • 8
  • Project work
  • 40
  • Preparation
  • 93
  • Exam
  • 25
  • Laboratory
  • 15
  • Theory exercises
  • 4
  • English
  • 206