Preparation and Development of Drugs with Biotechnological Methods

A.Y. 2021/2022
Overall hours
Learning objectives
The main learning objective of this integrated course is to highlight the great power of biotechnological methods for the production of drugs as well as for the optimization of existing drugs and the development of new drugs. The course aims at developing critical skills in relation to the pharmacokinetic issues that may limit the efficacy of biotechnological drugs; the possible chemical or biotechnological modifications useful to tune up the pharmacokinetic parameters are analysed and discussed. The course is focused on two main classes of biotechnological compounds: recombinant proteins and natural products and their derivatives, obtained using biotechnological methods.
The course gives an overview of the main classes of biotechnological drugs, starting from the history of their development, through the study of the structure-activity relationship until the development of new derivatives characterized by a better pharmacological profile, including also some examples of drugs that are currently under clinical evaluation.
In parallel, the course analyzes the strategies, based on the use of biocatalysis and industrial biotechnology, for the large scale production of biologically active natural compounds (traditionally obtained from natural sources by conventional fermentation and/or extraction processes), or new derivatives with improved pharmacological profiles.
Expected learning outcomes
By the end of the course, students will have to know the main structural features of each class of drugs studied and they should be able to critically discuss the structure-activity relationships. In particular, they should be able to recognize the essential pharmacophoric groups and to discuss the possible modifications useful to optimize the pharmacokinetic and pharmacodynamic properties. Students should be able to propose a biotechnological method useful for the preparation of a given compound as well as the most adequate methods for structural modifications aiming at the optimization of the biological activity.
Finally, students should be able to correctly understand the questions posed during the final test, being able to choose, elaborate and logically connect the information acquired within the integrated course.
Course syllabus and organization

Single session

Lesson period
Second semester
More specific information on the delivery modes of training acivities for academic year 2021/22 will be provided over the coming months, based on the evolution of the public health situation.
Course syllabus
The course deals with two main classes of biotechnological compounds: recombinant proteins and natural products and their derivatives obtained using biotechnological methods.
In details, the following topics will be discussed:

1) Natural products and their derivatives obtained using biotechnological methods.

- Secondary metabolism, biosynthetic pathways (lantapeptides, non-ribosomal peptides, aromatic and complex poliketides), gene clusters, regulation, strain improvement (mutagenesis and metabolic engineering) fermentation process and product recovery.
- Discovery, study of the structure-activity relationship and structural modifications for the optimization of the pharmacological profile.
- Combination of biotechnological and chemical methods for the synthesis of new analogs of natural products. Definition and examples of semisynthesis, precursor-directed biosynthesis and mutasynthesis.
- Biocatalytic methods for the semisynthesis or for the structural modification of natural products: relevance within the pharmaceutical field, biocatalytic techniques, protein engineering, enzyme immobilization.
- Bioconjugation methods for the improvement of the pharmacokinetic profile of small molecules.

Classes of drugs under study: beta lactam antibiotics, anthracyclines, statines, taxoids and artemisinin.

Recombinant proteins and peptidic drug

- Microbial cells for the production of recombinant proteins: host selection; strategies to improve productivity and secretion efficiency; bacterial protein expression systems (E. coli); eukaryotic protein expression systems (yeasts and filamentous fungi).
- Insulin and modified long-acting and short-acting insulins; insulin receptor: ligand-receptor interactions and discovery of small molecoles with insulino-mimetic properties. Incretinomimetics (GLP-1 analogs) and DPP-4 inhibitors.
- Growth hormone; GH receptor: ligand-receptor interactions; GHRH analogs; GHSR ligands (ghrelin and GHRP peptides); design of GH antagonists (Pegvisomant); other approaches for the treatment of acromegaly: design of somatostatin analogues.
- Cytokines: recombinant IL-2; Denileukin diftitox; recombinant IL-1 antagonist; Interferons, Peg-interferons and Albuferon.
- Examples of industrial production of heterologous proteins.
- Pharmacokinetic limitations associated to peptides and proteins and strategies for the controlled and sustained release.
Prerequisites for admission
- Background in Medicinal Chemistry , in particular the following general topics: drug targets, pharmacodynamics and pharmacokinetics. For those students who did not previously attended a Medicinal Chemistry course, the following text is warmly recommended: Graham L. Patrick CHIMICA FARMACEUTICA, Integrated edition by Gabriele Costantino, EdiSES (Parts A, B and C).
- Basic knowledge of Microbiology and Biotechnology of fermentations, in particular microbial metabolism and fermentation techniques. For those students who are not familiar with these topics, it is recommended to contact the teacher who will provide the students with the appropriate material for personal study.
Teaching methods
Frontal lessons. The two teachers will alternate in order to better integrate the different topics of the course.
Teaching Resources
- Power point presentations of the lessons, as pdf file, are available on the Ariel platform.
- Additional educational material may be suggested by the teacher during the lessons and made available through the Ariel platform.
-Suggested text-books:
1. G. L. Patrick: Chimica Farmaceutica Ed. EdiSES- Napoli (2015).
2. S. Donadio, G. Marino: Biotecnologie Microbiche - Casa Editrice Ambrosiana
Assessment methods and Criteria
The exam is a written test (2 hour time limit) including 4 open questions on the topics of the integrated course. In order to pass the exam, the student must answer to all four questions demonstrating a sufficient level of preparation. The evaluation will take into consideration the student's ability to correctly understand the questions and chose, elaborate and interconnect the information and knowledge acquired during the course, using an appropriate scientific language. The exam pass mark is 18/30.
Development of drugs with biotechnological methods
Lessons: 40 hours
Professor: Conti Paola
Preparation of drugs with biotechnological methods
Lessons: 32 hours
Professor: Gandolfi Raffaella