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New Modalities for Drug Design

Leipzig, 06.01.2020

Marcel Wygas, Sabine Fürst

New Modalities for Drug Design

Fakultät für Lebenswissenschaften, Institut für Biochemie

Why are new modalities necessary?

Not all biological targets can be applied (e.g. protein-

protein interactions)

Disadvantages in stability, proteolytic properties,…

Combine compounds of biologics and small moleculs

Access to novel areas of chemical space

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New Modalities for Drug Design

Fakultät für Lebenswissenschaften, Institut für Biochemie

Peptide-based approaches

Peptidomimetics

Small protein-like chain designed to mimic a peptide

4 classes:

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New Modalities for Drug Design

Fakultät für Lebenswissenschaften, Institut für Biochemie

Peptide-based approaches

- Mimetics of β-strands and β-sheets

β-hairpin = combination of two antiparallel β-strands

connected through a turn

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New Modalities for Drug Design

Fakultät für Lebenswissenschaften, Institut für Biochemie

Peptide-based approaches

- Mimetics of α-helices

N-terminal cap: artificial capping motif, e.g. hydrogen

bond surrogated (HBS)

Structural mimetics: replacement of entire backbone

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New Modalities for Drug Design

Fakultät für Lebenswissenschaften, Institut für Biochemie

Peptide-based approaches

- Mimetics of α-helices: Stapled Peptides

Methylation of α-carbon atoms + introduction of covalent

side to side chain cross-links

Incorporation of α-methyl-α-alkenylamino acids

Ring-closing metathesis (RCM)

Multiple staples

stitched peptide

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New Modalities for Drug Design

Fakultät für Lebenswissenschaften, Institut für Biochemie

Peptide-based approaches

- Mimetics of α-helices: Stapled Peptides

Staples can interact with target protein

loosely

at peptide/protein interface

directly in protein binding

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New Modalities for Drug Design

Fakultät für Lebenswissenschaften, Institut für Biochemie

Peptide-based approaches

- Mimetics of α-helices: Foldamers

non-natural oligomeric structures with predictable folding

propensities

major backbone alterations

Introduction of modified amino acids increases

proteolytic stability

β-peptides, α/β-peptides & peptoids

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New Modalities for Drug Design

Fakultät für Lebenswissenschaften, Institut für Biochemie

Peptide-based approaches

- Bicyclic Peptides

increased rigidity,

metabolic stability and

target specificity

Applications:

Therapeutics &

Diagnostics

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New Modalities for Drug Design

Fakultät für Lebenswissenschaften, Institut für Biochemie

Peptide-based approaches

- Aptamers

Artificial molecules selected from library ( evolutionary

approach)

bind specific targets molecules

Applications: Therapeutics (PPI) & Diagnostics

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New Modalities for Drug Design

Fakultät für Lebenswissenschaften, Institut für Biochemie

Oligonucleotide-based approaches

- Aptamers

Short DNA/RNA strands (25-90b)

Distinct conformations and interactions

Antibody like application

Advantages: stability, synthetic good yields

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New Modalities for Drug Design

Fakultät für Lebenswissenschaften, Institut für Biochemie

Oligonucleotide-based approaches

- Aptamers

Generation SELEX-method

dsDNA libraries

Scan for homology + combination

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New Modalities for Drug Design

Fakultät für Lebenswissenschaften, Institut für Biochemie

Oligonucleotide-based approaches

- Aptamers

Fields of application:

Therapy

Drug delivery

Bioassays( diagnostics)

direct (amplification)

sandwich (more than one aptamer)

competitive (monitoring)

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New Modalities for Drug Design

Fakultät für Lebenswissenschaften, Institut für Biochemie

Oligonucleotide-based approaches

- Translation

modRNA

RNA-modulation

Translation

miRNA pathway

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New Modalities for Drug Design

Fakultät für Lebenswissenschaften, Institut für Biochemie

Oligonucleotide-based approaches

- ASO + siRNA

Antisense oligonucleotides (ASO) + siRNA

16-20b

Binding of mRNA (Translation ) or miRNA (Translation )

Influence on one (mRNA) or more genes (miRNA)

Inhibition/degradation

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New Modalities for Drug Design

Fakultät für Lebenswissenschaften, Institut für Biochemie

Oligonucleotide-based approaches

- Ribozymes + gene editing

Enzyme like activity

(Cleavage of RNA)

Influence on genes

(Cas9-approach)

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New Modalities for Drug Design

Fakultät für Lebenswissenschaften, Institut für Biochemie

Oligonucleotide-based approaches

- Chemical Modifications

Short t1/2 (backbone cleavage, kidney clearance)

Modifications to improve pharmacokinetic properties

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New Modalities for Drug Design

Fakultät für Lebenswissenschaften, Institut für Biochemie

Oligonucleotide-based approaches

- Gapmers

Problem: 2'-OH modification decreases RNase H cleavage

Solution: Gapmers

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New Modalities for Drug Design

Fakultät für Lebenswissenschaften, Institut für Biochemie

Mixed Modalities

Improvement

Synergy

Polypharma-

cology

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New Modalities for Drug Design

Fakultät für Lebenswissenschaften, Institut für Biochemie

Mixed Modalities

- Target delivery: Peptides – small molecules

Lipids/fatty acids:

pharmacokinectics,

potency

Homing moieties:

cell penetrating

peptides (CPP)

"trojan horses"

blood-brain barrier

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New Modalities for Drug Design

Fakultät für Lebenswissenschaften, Institut für Biochemie

Mixed Modalities

- Target delivery: Oligonucleotides

Accumulation in kidney

and liver, poor cell

penetration

Carbohydrates

Lipids

Small molecules

Peptides

(Aptamers)

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New Modalities for Drug Design

Fakultät für Lebenswissenschaften, Institut für Biochemie

Mixed Modalities

- Synergistic approaches

Approaches for

challenging targets

Potency , stability

Resistance

(Cyclic) peptides

Small molecules

Oligonucleotides

Polypharmacology

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New Modalities for Drug Design

Fakultät für Lebenswissenschaften, Institut für Biochemie

Mixed Modalities

- PROTACs

Proteolysis-targeting chimeras (PROTACs)

Bifunctional

Protein degradation

Ubiquitin-proteasome-

system

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New Modalities for Drug Design

Fakultät für Lebenswissenschaften, Institut für Biochemie

Summary - Outlook

Many new strategies / improvement of already known

strategies (therapeutic range)

Still problems to overcome

Cell/tissue penetration

intracellular fate (endosome)

metabolic stability,

Safety

regulatory requirements

high production costs

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THANK YOU FOR YOUR

ATTENTION!