new modalites for drug design - uni-leipzig.de · new modalities for drug design fakultät für...
TRANSCRIPT
![Page 1: New Modalites for Drug Design - uni-leipzig.de · New Modalities for Drug Design Fakultät für Lebenswissenschaften, Institut für Biochemie Peptide-based approaches - Mimetics of](https://reader033.vdocuments.us/reader033/viewer/2022053005/5f091ffb7e708231d42558c1/html5/thumbnails/1.jpg)
New Modalities for Drug Design
Leipzig, 06.01.2020
Marcel Wygas, Sabine Fürst
![Page 2: New Modalites for Drug Design - uni-leipzig.de · New Modalities for Drug Design Fakultät für Lebenswissenschaften, Institut für Biochemie Peptide-based approaches - Mimetics of](https://reader033.vdocuments.us/reader033/viewer/2022053005/5f091ffb7e708231d42558c1/html5/thumbnails/2.jpg)
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
2
![Page 3: New Modalites for Drug Design - uni-leipzig.de · New Modalities for Drug Design Fakultät für Lebenswissenschaften, Institut für Biochemie Peptide-based approaches - Mimetics of](https://reader033.vdocuments.us/reader033/viewer/2022053005/5f091ffb7e708231d42558c1/html5/thumbnails/3.jpg)
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:
3
![Page 4: New Modalites for Drug Design - uni-leipzig.de · New Modalities for Drug Design Fakultät für Lebenswissenschaften, Institut für Biochemie Peptide-based approaches - Mimetics of](https://reader033.vdocuments.us/reader033/viewer/2022053005/5f091ffb7e708231d42558c1/html5/thumbnails/4.jpg)
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
4
![Page 5: New Modalites for Drug Design - uni-leipzig.de · New Modalities for Drug Design Fakultät für Lebenswissenschaften, Institut für Biochemie Peptide-based approaches - Mimetics of](https://reader033.vdocuments.us/reader033/viewer/2022053005/5f091ffb7e708231d42558c1/html5/thumbnails/5.jpg)
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
5
![Page 6: New Modalites for Drug Design - uni-leipzig.de · New Modalities for Drug Design Fakultät für Lebenswissenschaften, Institut für Biochemie Peptide-based approaches - Mimetics of](https://reader033.vdocuments.us/reader033/viewer/2022053005/5f091ffb7e708231d42558c1/html5/thumbnails/6.jpg)
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
6
![Page 7: New Modalites for Drug Design - uni-leipzig.de · New Modalities for Drug Design Fakultät für Lebenswissenschaften, Institut für Biochemie Peptide-based approaches - Mimetics of](https://reader033.vdocuments.us/reader033/viewer/2022053005/5f091ffb7e708231d42558c1/html5/thumbnails/7.jpg)
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
7
![Page 8: New Modalites for Drug Design - uni-leipzig.de · New Modalities for Drug Design Fakultät für Lebenswissenschaften, Institut für Biochemie Peptide-based approaches - Mimetics of](https://reader033.vdocuments.us/reader033/viewer/2022053005/5f091ffb7e708231d42558c1/html5/thumbnails/8.jpg)
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
8
![Page 9: New Modalites for Drug Design - uni-leipzig.de · New Modalities for Drug Design Fakultät für Lebenswissenschaften, Institut für Biochemie Peptide-based approaches - Mimetics of](https://reader033.vdocuments.us/reader033/viewer/2022053005/5f091ffb7e708231d42558c1/html5/thumbnails/9.jpg)
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
9
![Page 10: New Modalites for Drug Design - uni-leipzig.de · New Modalities for Drug Design Fakultät für Lebenswissenschaften, Institut für Biochemie Peptide-based approaches - Mimetics of](https://reader033.vdocuments.us/reader033/viewer/2022053005/5f091ffb7e708231d42558c1/html5/thumbnails/10.jpg)
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
10
![Page 11: New Modalites for Drug Design - uni-leipzig.de · New Modalities for Drug Design Fakultät für Lebenswissenschaften, Institut für Biochemie Peptide-based approaches - Mimetics of](https://reader033.vdocuments.us/reader033/viewer/2022053005/5f091ffb7e708231d42558c1/html5/thumbnails/11.jpg)
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
11
![Page 12: New Modalites for Drug Design - uni-leipzig.de · New Modalities for Drug Design Fakultät für Lebenswissenschaften, Institut für Biochemie Peptide-based approaches - Mimetics of](https://reader033.vdocuments.us/reader033/viewer/2022053005/5f091ffb7e708231d42558c1/html5/thumbnails/12.jpg)
New Modalities for Drug Design
Fakultät für Lebenswissenschaften, Institut für Biochemie
Oligonucleotide-based approaches
- Aptamers
Generation SELEX-method
dsDNA libraries
Scan for homology + combination
12
![Page 13: New Modalites for Drug Design - uni-leipzig.de · New Modalities for Drug Design Fakultät für Lebenswissenschaften, Institut für Biochemie Peptide-based approaches - Mimetics of](https://reader033.vdocuments.us/reader033/viewer/2022053005/5f091ffb7e708231d42558c1/html5/thumbnails/13.jpg)
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)
13
![Page 14: New Modalites for Drug Design - uni-leipzig.de · New Modalities for Drug Design Fakultät für Lebenswissenschaften, Institut für Biochemie Peptide-based approaches - Mimetics of](https://reader033.vdocuments.us/reader033/viewer/2022053005/5f091ffb7e708231d42558c1/html5/thumbnails/14.jpg)
New Modalities for Drug Design
Fakultät für Lebenswissenschaften, Institut für Biochemie
Oligonucleotide-based approaches
- Translation
modRNA
RNA-modulation
Translation
miRNA pathway
14
![Page 15: New Modalites for Drug Design - uni-leipzig.de · New Modalities for Drug Design Fakultät für Lebenswissenschaften, Institut für Biochemie Peptide-based approaches - Mimetics of](https://reader033.vdocuments.us/reader033/viewer/2022053005/5f091ffb7e708231d42558c1/html5/thumbnails/15.jpg)
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
15
![Page 16: New Modalites for Drug Design - uni-leipzig.de · New Modalities for Drug Design Fakultät für Lebenswissenschaften, Institut für Biochemie Peptide-based approaches - Mimetics of](https://reader033.vdocuments.us/reader033/viewer/2022053005/5f091ffb7e708231d42558c1/html5/thumbnails/16.jpg)
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)
16
![Page 17: New Modalites for Drug Design - uni-leipzig.de · New Modalities for Drug Design Fakultät für Lebenswissenschaften, Institut für Biochemie Peptide-based approaches - Mimetics of](https://reader033.vdocuments.us/reader033/viewer/2022053005/5f091ffb7e708231d42558c1/html5/thumbnails/17.jpg)
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
17
![Page 18: New Modalites for Drug Design - uni-leipzig.de · New Modalities for Drug Design Fakultät für Lebenswissenschaften, Institut für Biochemie Peptide-based approaches - Mimetics of](https://reader033.vdocuments.us/reader033/viewer/2022053005/5f091ffb7e708231d42558c1/html5/thumbnails/18.jpg)
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
18
![Page 19: New Modalites for Drug Design - uni-leipzig.de · New Modalities for Drug Design Fakultät für Lebenswissenschaften, Institut für Biochemie Peptide-based approaches - Mimetics of](https://reader033.vdocuments.us/reader033/viewer/2022053005/5f091ffb7e708231d42558c1/html5/thumbnails/19.jpg)
New Modalities for Drug Design
Fakultät für Lebenswissenschaften, Institut für Biochemie
Mixed Modalities
Improvement
Synergy
Polypharma-
cology
19
![Page 20: New Modalites for Drug Design - uni-leipzig.de · New Modalities for Drug Design Fakultät für Lebenswissenschaften, Institut für Biochemie Peptide-based approaches - Mimetics of](https://reader033.vdocuments.us/reader033/viewer/2022053005/5f091ffb7e708231d42558c1/html5/thumbnails/20.jpg)
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
20
![Page 21: New Modalites for Drug Design - uni-leipzig.de · New Modalities for Drug Design Fakultät für Lebenswissenschaften, Institut für Biochemie Peptide-based approaches - Mimetics of](https://reader033.vdocuments.us/reader033/viewer/2022053005/5f091ffb7e708231d42558c1/html5/thumbnails/21.jpg)
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)
21
![Page 22: New Modalites for Drug Design - uni-leipzig.de · New Modalities for Drug Design Fakultät für Lebenswissenschaften, Institut für Biochemie Peptide-based approaches - Mimetics of](https://reader033.vdocuments.us/reader033/viewer/2022053005/5f091ffb7e708231d42558c1/html5/thumbnails/22.jpg)
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
22
![Page 23: New Modalites for Drug Design - uni-leipzig.de · New Modalities for Drug Design Fakultät für Lebenswissenschaften, Institut für Biochemie Peptide-based approaches - Mimetics of](https://reader033.vdocuments.us/reader033/viewer/2022053005/5f091ffb7e708231d42558c1/html5/thumbnails/23.jpg)
New Modalities for Drug Design
Fakultät für Lebenswissenschaften, Institut für Biochemie
Mixed Modalities
- PROTACs
Proteolysis-targeting chimeras (PROTACs)
Bifunctional
Protein degradation
Ubiquitin-proteasome-
system
23
![Page 24: New Modalites for Drug Design - uni-leipzig.de · New Modalities for Drug Design Fakultät für Lebenswissenschaften, Institut für Biochemie Peptide-based approaches - Mimetics of](https://reader033.vdocuments.us/reader033/viewer/2022053005/5f091ffb7e708231d42558c1/html5/thumbnails/24.jpg)
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
24
![Page 25: New Modalites for Drug Design - uni-leipzig.de · New Modalities for Drug Design Fakultät für Lebenswissenschaften, Institut für Biochemie Peptide-based approaches - Mimetics of](https://reader033.vdocuments.us/reader033/viewer/2022053005/5f091ffb7e708231d42558c1/html5/thumbnails/25.jpg)
THANK YOU FOR YOUR
ATTENTION!