University of Indonesia / Jakarta

March 6th 2019

Biotechnology in Drug Development

Hans-Jürgen Mägert, Anhalt University of Applied Sciences, Köthen, Germany

Biotechnology in Drug Development

1. INTRODUCTION

What is Pharmaceutical Biotechnology, history, market potential of

pharmaceuticals

2. MAIN PART

Basics of Pharmaceutical Biotechnology

– Medical needs
– Target identification / validation
– Compound libraries
– Assay establishment and agent screening
– Lead optimization
– Recombinant production of pharmaceutical proteins
– Safety Aspects
Lead structure (lead compound, lead molecule): a
compound that has been shown to bind to and/or
inhibit and/or activate a validated target from a (high-
throughput) screen

This lead structure mostly still has to be optimized

=> „lead optimization“
 Lead Optimization

What shall be optimized?

– Effect (activity)

– Selectivity

– Size (reduction)

– Bioavailability (kinetics/degree of resorption, stability)

– Toxicity / side effects (decrease)

 Lead optimization – strategies

– Rational design
(based on known 3D structure of target, computer-aided)

– Directed evolution
(accidental in vitro mutagenesis by incorrect PCR –> test for
best candidate)

– Combinatorial synthesis
(synthesis of variants of the lead –> test for best candidate)
Rational design for identification and optimization
of lead structures
 Combinatorial Synthesis

– Combinatorial synthesis of compound libraries stands some-

where in between library construction and lead optimization

– Particularly suitable for peptidic drug candidates (generation

of peptide libraries)

– Strategy may be followed for varying just a selected number

of amino acids not (so) essential for peptide function

– Most suitable for identification of high activity compounds is

„iterative deconvolution“
Strategies of combinatorial synthesis
 Parallel Synthesis

Advantage: each drug candidate is represented as a pure substance

Disadvantage: large number of synthesis steps
Advantage: less synthesis steps than in parallel synthesis
Disadvantage: drug candidates are represented within a mix (not pure)
Advantage: most active compound may be identified with few synthesis steps
Disadvantage: library may not be used for other applications (just for one)
 Lead Optimization – Activity / Effect

John Topliss‘ rule:

– Replace one substituent of a lead structure

– If the effect is improved replace substituent with another exhibiting

similar but stronger properties

– If the effect is impaired replace substituent with another exhibiting

properties which stand in the opposite direction

– e.g. if a replacement of a bromine atom with a chlorine atom would

lead to a better effect the next step would be the replacement of a
chlorine atom with a fluorine atom
Biotechnology in Drug Development

1. INTRODUCTION

What is Pharmaceutical Biotechnology, history, market potential of

pharmaceuticals

2. MAIN PART

Basics of Pharmaceutical Biotechnology

– Medical needs
– Target identification / validation
– Compound libraries
– Assay establishment and agent screening
– Lead optimization
– Recombinant production of pharmaceutical proteins
– Safety Aspects
Thank you very much for your attention!