Peptide and Protein Therapeutics · employed in peptides and proteins. •D-peptides are stable...
Transcript of Peptide and Protein Therapeutics · employed in peptides and proteins. •D-peptides are stable...
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Peptide and Protein Therapeutics
Seminar – Bioorganic Chemistry
11.12.2019
•Chun-Chiao Yang
•Diego Garcia
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Peptide synthesis
Ahrens, V. M.; Bellmann-Sickert, K.; Beck-Sickinger, A. G. Peptides and PeptideConjugates: Therapeutics on the Upward Path. Future Medicinal Chemistry 2012, 4(12), 1567–1586. https://doi.org/10.4155/fmc.12.76.
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Pros & Cons
Small molecules
• Low molecular weight
Cost-effective
Few synthetic steps
Oral availability
Easy crossing of biologicalmembranes
Accumulation
Toxic metabolites
Peptides
• Sequences of ≈ 20 amino acids
High cost
More complex synthetic steps
Intramuscular administration
High selectivity and affinity
Hydrolysis → nontoxic products
Less drug-drug interactions
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Stabilization of peptidic drugs
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Stabilization of peptidic drugsProblem:
Lack in vivo stability and limitedaccess to the intracellular space.
↓
Peptide stabilization: Anymodification applied increase invivo stability.
Modification of the peptidesequence or attachment ofstabilizing agents to amino acid sidechains.
AMINOPEPTIDASE
PDB ID: 1XJO
DIPEPTIDYL PEPTIDASE
PDB ID: 3JYH
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PEGylation (polyethylenglycol)
• Increases water solubility
• Shields from proteases
• Improves bio distribution
• Lowers allergenic properties
• Size 2-40 kDa, increases the mw• ↓ Renal filtration, ↑Half-life
• PEGs for modification arecommercially available, with differentfunctionalities.
Disadvantage:
• No enzyme able to degrade themolecule is known.
• Adagen®, Oncaspar® and Krystexxa®:PEGylate enzymes.
• Cimzia®: TNF-α-blocking antibodyfragment to treat Chron’s disease andrheumatoid arthritis.
• Neulasta®, Mircera® and Somavert®:growth factors.
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D-amino acids
• Naturally, only L-amino acids areemployed in peptides andproteins.
• D-peptides are stable towardsproteolysis.
• Binds to the target in an equalmanner as natural all-L-peptides
D-phenylalanine in humancalcitonin derivatives as cell-penetrating peptides in drug-delivery.
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Lipidation
Acylation of compounds with fattyacids.
• Higher affinity to albumin.• ↑ time of the drug in the blood, ↓ renal
and hepatic clearance.
Insuline
• C10
• C12
• C14
Levemir®
Lipidated insulin variant is available as along-acting therapeutic
Combinated with D-amino acids, protectpeptides from peptidases.
• Gonadotropinreleasing hormone.
Decapeptide containing a D- and an L-cysteine, cyclized via a thioether bridge.
Cyclization
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Integration of non-natural amino acids
N-methyl amino acids Peptoids
Reduced peptidesβ-peptides
(2) Seebach, D.; Matthews, J. L. β-Peptides: A Surprise at Every Turn. Chem. Commun. 1997, No. 21, 2015–2022. https://doi.org/10.1039/A704933A. (3) Automated Synthesis of Peptoids and Peptoid-PeptideHybrids http://cem.com/de/automated-synthesis-of-peptoids-and-peptoid-peptide-hybrids (accessed Dec 4, 2019). (4) Andersson, H.; Hallberg, M. Discovery of Inhibitors of Insulin-Regulated Aminopeptidase asCognitive Enhancers. International journal of hypertension 2012, 2012, 789671. https://doi.org/10.1155/2012/789671.
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PASylation®
Conjugation with an at least 100amino acid random sequencecomprising the three amino acidsproline, alanine and serine.
Recombinant vectors encodingthe PAS-sequence.
• Increases resistance againstproteases.
• Ability of renal cleaved.
• Highly soluble.
• Nontoxic and non-immunogenic.
• Easy to purify during synthesis.
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HESylation®
Fusion with hydroxyethyl starch (HES)
Linked to cysteine residues, via glycosylated side chains and enzymatically by transglutaminase reactions derivatives.
Better biodegradability than PEG.
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Approved peptidic therapeutics
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AntibioticsGramicidin D
Linear peptide, which is a mixture of three gramicidines (A–C).
Daptomycin
Val-Gly-Ala-D-
Leu-Ala-D-Val-
Val-Val-Trp-D-
Leu-Trp-D-
Leu-Trp-D-
Leu-Trp-Gly
(5) Andersson, H.; Hallberg, M. Discovery of Inhibitors of Insulin-Regulated Aminopeptidase as CognitiveEnhancers. International journal of hypertension 2012, 2012, 789671. https://doi.org/10.1155/2012/789671.(6) Steenbergen, J.; Alder, J.; Thorne, G.; Tally, F. Daptomycin: A Lipopeptide Antibiotic for the Treatment ofSerious Gram-Positive Infections. The Journal of antimicrobial chemotherapy 2005, 55, 283–288.https://doi.org/10.1093/jac/dkh546.
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Gonadotropin-releasing hormone receptor antagonistAbarelix, Cetrorelix, Goserelin and Leuprolide
Suppression of gonadotropinsecretion upon binding in acompetitive manner, blocking theaction of agonists.
Contain single amino acidreplacements in their sequence.
• During fertility treatment,prevent the premature surge ofluteinizing hormone.
• Lead to a decrease oftestosterone levels
(7) National Center for Biotechnology Information. PubChem Database. Abarelix, CID=16131215,https://pubchem.ncbi.nlm.nih.gov/compound/Abarelix (accessed on Dec. 4, 2019)
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Anticoagulants
Bivalirudin and Lepirudin
Derivatives of peptides producedin medicinal leeches’ saliva.
Treatment of heparin inducedthrombocytopenia by inhibition ofthrombin.
(8) Steenbergen, J.; Alder, J.; Thorne, G.; Tally, F. Daptomycin: A Lipopeptide Antibiotic for the Treatment of Serious Gram-Positive Infections. The Journal of antimicrobial chemotherapy 2005, 55, 283–288.https://doi.org/10.1093/jac/dkh546. (9) Warkentin, T. E. . CHAPTER 44 - The Diagnosis and Management of Heparin-Induced Thrombocytopenia. In The Vein Book; Bergan, J. J., Ed.; Academic Press: Burlington, 2007; pp 395–403. https://doi.org/10.1016/B978-012369515-4/50047-8.
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DiabetesExenatide
Glucagon-like peptide 1(GLP 1), resistant to dipeptidyl peptidase IV resistant.Agonist on the GLP1-receptor. • Stimulation of glucose-dependent
insulin secretion.• Suppression of glucagon secretion.• Prolonged residence times of food
in the stomach.• Reduction in food intake.
Liraglutide
• Lipidated lysine residue.• Attaches to serum albumin to
increase the half-life.• After binding to the glucagon
receptor, leads to an activation of glycogen phosphorylase and a release of glucose-1-phosphate into the bloodstream.
• It is used in diabetes patients in the treatment of hypoglycemia after insulin overdosing.
(10) Chia, C.; Egan, J. Role and Development of GLP-1 ReceptorAgonists in the Management of Diabetes. Diabetes, metabolicsyndrome and obesity : targets and therapy 2009, 2, 37.https://doi.org/10.2147/DMSOTT.S4283.
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Terapeutic peptides in clinical trailsBioorganic Chemistry
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Clinical phases Phase I (20-100 People)
Pharmacokinetics, pharmacodynamics and general safety of drug.
Phase II (100-300 People) Small-scale study to investigate the drug effectiveness and side effect.
Phase III (300-3000 People) Large-scale study to investigate the drug effectiveness and side effect.
Phase IV (anyone seeking for treatment from physician) Post Marketing Surveillance.
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Examples of peptidic vaccines andimmunotherapeutics Melanomas
Glycoprotein 100-derived peptide
Cytostatic temozolomide with Telomerase peptide vaccine GV1001
Breast Cancer Peptide AE37
Peptide GP2
Obesity Obinepitide
TM30339
Pramlintide
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Temozolomide with telomerase peptide vaccine Combination therapy
Try to enhance the immunologic response
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Kyte JA, Gaudernack G, Dueland S et al. Clin. Cancer Res. 17(13), 4568–4580 (2011)
25 Collected patients
T-cell responses were detected
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Not immunotherapeutics approach and what next…?
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Liu Z, Wang F, Chen X. Integrin alpha(v)beta(3)-Targeted Cancer Therapy. Drug Dev Res. 2008
Intergrin targeting may be an alternative.
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Basic research on future therapeuticpeptides
Bioorganic Chemistry
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What can we do more with peptides?
targetGPCR
agonists
inverse agonists
antagonists
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https://www.nature.com/scitable/topicpage/gpcr-14047471/
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G-protein-coupled receptor (GPCR)
Signal molecule
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Intelligent linker strategies
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Functions of peptides
peptidetherapeutics
As drug
As a carrier
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Intelligent linkers Acetal linker
Disufide linker
Ester linker
Hydrazone linker
GFLG sequence
Valine-citrulline sequence
Furin cleavage site
Dipeptidyl peptidase IV cleavage site
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Acetal linker
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Easy to synthesis
PH-dependent hydrolysis
Bifunction
Ex: mesoporous silica withmelittin
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Hydrazone linker Acid labile linkers
Peptides amphiphiles
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Ester linker Can be cleavage by enzyme or pH change
Easy to degrade in blood
Ex: nanotubes fused to therapeutic molecule
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Liu Z, Chen K, Davis C, et al. Drug delivery with carbon nanotubes for in vivo cancer treatment. Cancer Res. 2008
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Linker is cleavaged by special enzyme
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GFLG Sequence Valine-citrulline SequenceFurin cleavage site
Cathepsin B
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Dipepeptidyl peptidase IV (Dppiv)
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Diez-Torrubia A, Balzarini J, Andrei G et al. Dipeptidyl peptidase IV dependent water-soluble prodrugs of highly lipophilic bicyclicnucleoside analogues. J. Med. Chem.(2011)
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Peptidic therapeutics can do more…
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Conclusion
• Due to the limit of small-molecules drugs and their toxicity, a newway of treatment has been developed with peptide drugs.
• Stabilization techniques and linkers are crucial for the growth of thisfield.
• In last decade there are more and more new approved peptide-drugs.
• Stability and the cost of peptide drugs are still having challenges.
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Thank you!