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New Modalities for Drug Design Leipzig, 06.01.2020 Marcel Wygas, Sabine Fürst
Transcript of New Modalites for Drug Design - uni-leipzig.de · New Modalities for Drug Design Fakultät für...
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!
