Peptide therapeutics explained

Peptide therapeutics are peptides or polypeptides (oligomers or short polymers of amino acids) which are used to for the treatment of diseases. Naturally occurring peptides may serve as hormones, growth factors, neurotransmitters, ion channel ligands, and anti-infectives; peptide therapeutics mimic such functions. Peptide Therapeutics are seen as relatively safe and well-tolerated as peptides can be metabolized by the body.[1]

Examples

The current highest selling marketed diabetic drug Liraglutide, incorporates a lipid chain to extend plasma circulation and prolong bioavailability.[2] [3] Liraglutide is a GLP-1 agonist drug that self-assembles into an alpha-helical structure, and it requires once a day administration.[4] Lipid conjugation of a palmitoyl chain to a lysine residue at position 26 of Liraglutide results in an extended half-life (around 13–14 hours) in the blood. This is due to the palmitoyl chain allowing non covalent binding to albumin, which delays proteolytic attack by DPP IV and also rapid renal clearance. Furthermore, the addition of the lipid chain could further prolong half-life by sterically hindering the DPP IV enzyme from degradation.[5]

Another peptide known to self-assemble is the octapeptide Lanreotide. This compound is a synthetic analogue of the peptide hormone somatostatin and it is used to treat acromegaly[6] (a condition where the body produced too much growth hormone). In water, Lanreotide self-assembles into monodisperse liquid crystalline nanotubes. The nanotubes are made up of dimers that self-assemble into a 2D crystal, which is held together by lateral chain interactions, and also by antiparallel ß-sheets.[6] [7]

Further insight into how self-assembly and peptide hormones are related has been provided by studies on self-assembling amyloid structures formed by peptide hormones and neuropeptides. Peptide hormones and neuropeptides form dense-cored aggregates that pack into dense-core vesicles (DCVs), which are used to temporarily store peptide messengers in secretory cells.[8] When dense-core vesicles are triggered, they release the stored information into the blood or extracellular space,[9] resulting in amyloid disassembly, in order for action. Therefore, for these types of peptides, reversibility of peptide aggregation is essential for their function.

Increasing stability of peptide drugs

Many strategies have been employed to increase the stability of peptide drugs, because although they have so many desirable characteristics, they are short lived in the body as a result of rapid degradation and clearance. With half-lives of some peptides and proteins only being a few minutes, they are very ineffective in drug delivery.[10] Mechanisms involved in their clearance include peripheral blood mediated elimination by proteolysis, renal and hepatic elimination, and also receptor-mediated endocytosis.[11] One of the main reasons for such rapid clearance is molecular weight. Molecules that have a low molecular weight (40-50 kDa) are rapidly cleared by renal filtration via the glomerular filtration barrier (GBM) into the urine. As a result of this, increasing the size of a peptide drug is a good starting point to improve half-life.[12]

Peptide modifications to extend half-life include PEGylation, glycosylation, cyclization, serum albumin binding, and lipidation. PEGylation is the attachment of polyethylene glycol (PEG) chains to the peptide via covalent bonds, helping to increase molecular weight, and limit enzymatic degradation as a result of steric hindrance caused by adding the PEG.[13] PEGylation offers a number of benefits for pharmaceutical applications such as improved water solubility, high mobility in solution, as well as low toxicity and low immunogenicity. This does however depend on the molecular weight of the attached PEG.[14] [15] PEGylation as a method to improve half-life has been successfully demonstrated many times; in one example it was shown that site specific mono-PEGylation of GLP-1 led to a 16-fold increase in plasma half life time in rats.[16] On the other hand, covalently attaching PEG can often lead to loss of biological activity.[17]

Another chemical modification is the attachment of glycosyl (carbohydrate) units to the peptide to help with peptide delivery to target sites. The introduction of carbohydrates to peptides can alter the physiological properties, to improve bioavailability. Advantages of this technique include increased metabolic stability, and facilitated transport across cell membranes, although of the most favourable aspects is their ability to promote oral absorption.[18] Peptides have a very low oral availability (less than 1-2%),[19] [20] [21] as a result of insufficient absorption and rapid degradation and clearance, thus making this method an attractive one. N- and O-glycosylation in which carbohydrates are attached to the peptide are naturally occurring, where N-glycosylation occurs through the amine group of an asparagine residue to form an amide bond. O-glycosylation occurs via serine or threonine residues, where the oxygen atom on the side chain binds to the carbohydrate through an ether bond. There is also non-natural glycosylation, known as chemical glycosylation, which involves the attachment of carbohydrate units to different amino acid residues at the N-terminus of the peptide's sequence. A further way of carrying out glycosylation is by using enzymes, known as chemo-enzymatic glycosylation. This method is used for complex chemical synthesis.[22] [23] Chemical and chemo-enzymatic methods can be used for the synthesis of glycopeptides and glycoproteins.

Cyclization can also be used as a method to decrease proteolytic degradation and prolong half-life, to make the peptide conformation more rigid to hinder enzymatic cleavage. This method can however lead to loss of biological function due to the reduced flexibility making the peptide inactive.[24] For example, side chain to side chain cyclization between asparagine (position 8) and lysine (position 12), of a growth regulating factor (GRF) analogue was found to increase the half-life from 17 minutes to more than 2 hours.

Another way to extend half-life do is to bind serum albumin to the peptide. Human serum albumin is the most abundant plasma protein with a molecular weight of 66.4 kDa,[25] and it is involved in many essential bodily functions to maintain homeostasis. As a result, albumin binding would significantly increase the molecular weight of the peptide, restricting it from being filtered into the urine by the GBM. Serum albumin has an extraordinary long half-life of 2-4 weeks which is much longer than other plasma proteins,[26] due to it binding to the neonatal Fc receptor (FcRn). Fc receptors are proteins found on the surface of certain cells that help to protect the functions of the immune system, by binding to the Fc region of antibodies, which attach to pathogens and destroy them. This mechanism of the neonatal FcRn involves albumin binding to the FcRn in an acidic pH environment to divert it from degradation in the lysosomal compartment of the cell, and redirecting it to the plasma membrane, where it is released back into the blood plasma due to neutral pH.[27]

Lipidation is a further technique to use when improving peptide stability and half-life. Attaching a lipid chain to the peptide head group has been found to inhibit proteolytic attack due to the lipid chain non-covalently interacting with serum albumin to increase the molecular weight, thus reducing renal filtration. Studies on a lipidated analogue of insulin, detemir, revealed a prolonged action as a result of its affinity for human serum albumin.[28] As well as this, lipidation has been shown to enhance the interaction of peptides with cell membranes, allowing them to be up taken into the cell more readily compared to the peptide lacking the lipid moiety.[29] [30] There are three types of lipidation, and they differ based on the bond formation methods between the lipid and the peptide: amidation, esterification (S- or O-) and S-bond (ether or disulphide) formation. Amidation and O-esterification form strong covalent bonds that are irreversible, whereas the other two methods are weak and reversible covalent bonds. The method used, as well as the alkyl/lipid chain, position of lipidation, and the spacer used, all have significant impacts on physiochemical properties and bioactivity.[31] The level of lipophilicity can be significantly modulated by lipidation, and since lipophilicity is detrimental for the absorption, distribution, metabolism, and excretion of drugs, it provides a way of fine tuning peptides for use in therapeutics .

A study on lipidation and PEGylation on the GLP-1 peptide was carried out and the results showed that lipidation had no significant effect on peptide activity in vitro,[32] whereas PEGylation did, especially when the PEG is attached to internal amino acids of the peptide e.g. positions 20 and 21. The reduction in activity from PEGylation compared to lipidation is due to the loss of receptor affinity, and it is suggested that this is because of its increased molecular weight which causes steric hindrance.[33] [34]

Further readings and Books

  1. Implantable Technologies: Peptides and Small Molecules Drug Delivery
    1. ISBN: 9781839162220[35]
  2. Peptide-based Drug Discovery: Challenges and New Therapeutics
    1. ISBN: 9781782627326[36]
  3. Peptide Therapeutics: Strategy and Tactics for Chemistry, Manufacturing, and Controls
    1. ISBN: 9781788014335[37]
  4. Peptide Therapeutics: Strategy for Chemistry Manufacturing and Control (CMC)
    1. ISBN: 9781788014335[38]
  5. Peptides 2015; Proceedings of the 24th American Peptide Symposium
    1. ISBN: 9780983974154[39]
  6. Implantable Technologies: Peptides and Small Molecules Drug Delivery
    1. ISBN: 9781839162220[40]
  7. Peptide-based Drug Discovery: Challenges and New Therapeutics
    1. ISBN: 9781782627326[41]
  8. Comprehensive Medicinal Chemistry III - Volume 7: Biologics Medicine
    1. ISBN: 9780081022467[42]

Notes and References

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  3. Gao Z, Bai G, Chen J, Zhang Q, Pan P, Bai F, Geng P . Development, characterization, and evaluation of a fusion protein of a novel glucagon-like peptide-1 (GLP-1) analog and human serum albumin in Pichia pastoris . Bioscience, Biotechnology, and Biochemistry . 73 . 3 . 688–94 . March 2009 . 19270384 . 10.1271/bbb.80742 . 39307659 . free .
  4. Wang Y, Lomakin A, Kanai S, Alex R, Benedek GB . Transformation of oligomers of lipidated peptide induced by change in pH . Molecular Pharmaceutics . 12 . 2 . 411–9 . February 2015 . 25569709 . 10.1021/mp500519s .
  5. Frederiksen TM, Sønderby P, Ryberg LA, Harris P, Bukrinski JT, Scharff-Poulsen AM, Elf-Lind MN, Peters GH . 6 . Oligomerization of a Glucagon-like Peptide 1 Analog: Bridging Experiment and Simulations . Biophysical Journal . 109 . 6 . 1202–13 . September 2015 . 26340816 . 4576320 . 10.1016/j.bpj.2015.07.051 . 2015BpJ...109.1202F .
  6. Valéry C, Artzner F, Robert B, Gulick T, Keller G, Grabielle-Madelmont C, Torres ML, Cherif-Cheikh R, Paternostre M . 6 . Self-association process of a peptide in solution: from beta-sheet filaments to large embedded nanotubes . Biophysical Journal . 86 . 4 . 2484–501 . April 2004 . 15041685 . 1304096 . 10.1016/S0006-3495(04)74304-0 . 2004BpJ....86.2484V .
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  8. Nespovitaya N, Gath J, Barylyuk K, Seuring C, Meier BH, Riek R . Dynamic Assembly and Disassembly of Functional β-Endorphin Amyloid Fibrils . Journal of the American Chemical Society . 138 . 3 . 846–56 . January 2016 . 26699104 . 10.1021/jacs.5b08694 .
  9. Glombik M . April 2000 . Signal-mediated sorting of neuropeptides and prohormones:Secretory granule biogenesis revisited . Biochimie. 82. 4. 315–326. 10.1016/S0300-9084(00)00195-4. 10865120 .
  10. Werle M, Bernkop-Schnürch A . Strategies to improve plasma half life time of peptide and protein drugs . Amino Acids . 30 . 4 . 351–67 . June 2006 . 16622600 . 10.1007/s00726-005-0289-3 . 31092931 .
  11. Tang L, Persky AM, Hochhaus G, Meibohm B . Pharmacokinetic aspects of biotechnology products . Journal of Pharmaceutical Sciences . 93 . 9 . 2184–204 . September 2004 . 15295780 . 10.1002/jps.20125 .
  12. Tryggvason K, Wartiovaara J . How does the kidney filter plasma? . Physiology . 20 . 2 . 96–101 . April 2005 . 15772298 . 10.1152/physiol.00045.2004 .
  13. Hamley IW . PEG-peptide conjugates . Biomacromolecules . 15 . 5 . 1543–59 . May 2014 . 24720400 . 10.1021/bm500246w . 28954181 .
  14. Werle M, Bernkop-Schnürch A . Strategies to improve plasma half life time of peptide and protein drugs . Amino Acids . 30 . 4 . 351–67 . June 2006 . 16622600 . 10.1007/s00726-005-0289-3 . 31092931 .
  15. Bellmann-Sickert K, Elling CE, Madsen AN, Little PB, Lundgren K, Gerlach LO, Bergmann R, Holst B, Schwartz TW, Beck-Sickinger AG . 6 . Long-acting lipidated analogue of human pancreatic polypeptide is slowly released into circulation . Journal of Medicinal Chemistry . 54 . 8 . 2658–67 . April 2011 . 21410292 . 10.1021/jm101357e .
  16. Lee SH, Lee S, Youn YS, Na DH, Chae SY, Byun Y, Lee KC . Synthesis, characterization, and pharmacokinetic studies of PEGylated glucagon-like peptide-1 . Bioconjugate Chemistry . 16 . 2 . 377–82 . 2005-03-01 . 15769092 . 10.1021/bc049735+ .
  17. Harris JM, Chess RB . Effect of pegylation on pharmaceuticals . Nature Reviews. Drug Discovery . 2 . 3 . 214–21 . March 2003 . 12612647 . 10.1038/nrd1033 . 574824 .
  18. Moradi SV, Hussein WM, Varamini P, Simerska P, Toth I . Glycosylation, an effective synthetic strategy to improve the bioavailability of therapeutic peptides . Chemical Science . 7 . 4 . 2492–2500 . April 2016 . 28660018 . 5477030 . 10.1039/C5SC04392A .
  19. Mandal D, Nasrolahi Shirazi A, Parang K . Self-assembly of peptides to nanostructures . Organic & Biomolecular Chemistry . 12 . 22 . 3544–61 . June 2014 . 24756480 . 4038164 . 10.1039/C4OB00447G .
  20. Zhou P, Deng L, Wang Y, Lu JR, Xu H . Different nanostructures caused by competition of intra- and inter-β-sheet interactions in hierarchical self-assembly of short peptides . Journal of Colloid and Interface Science . 464 . 219–28 . February 2016 . 26619132 . 10.1016/j.jcis.2015.11.030 . 2016JCIS..464..219Z .
  21. Houston ME, Wallace A, Bianchi E, Pessi A, Hodges RS . Use of a conformationally restricted secondary structural element to display peptide libraries: a two-stranded alpha-helical coiled-coil stabilized by lactam bridges . Journal of Molecular Biology . 262 . 2 . 270–82 . September 1996 . 8831793 . 10.1006/jmbi.1996.0512 .
  22. Salamone S, Guerreiro C, Cambon E, André I, Remaud-Siméon M, Mulard LA . Programmed chemo-enzymatic synthesis of the oligosaccharide component of a carbohydrate-based antibacterial vaccine candidate . Chemical Communications . 51 . 13 . 2581–4 . February 2015 . 25569152 . 10.1039/C4CC08805K .
  23. Fujikawa K, Koizumi A, Hachisu M, Seko A, Takeda Y, Ito Y . Construction of a high-mannose-type glycan library by a renewed top-down chemo-enzymatic approach . Chemistry . 21 . 8 . 3224–33 . February 2015 . 25586968 . 10.1002/chem.201405781 .
  24. Räder AF, Reichart F, Weinmüller M, Kessler H . Improving oral bioavailability of cyclic peptides by N-methylation . Bioorganic & Medicinal Chemistry . 26 . 10 . 2766–2773 . June 2018 . 28886995 . 10.1016/j.bmc.2017.08.031. 29149595 . free .
  25. Ehrlich GK, Michel H, Truitt T, Riboulet W, Pop-Damkov P, Goelzer P, Hainzl D, Qureshi F, Lueckel B, Danho W, Conde-Knape K, Konkar A . 6 . Preparation and characterization of albumin conjugates of a truncated peptide YY analogue for half-life extension . Bioconjugate Chemistry . 24 . 12 . 2015–24 . December 2013 . 24251972 . 10.1021/bc400340z .
  26. Kontermann RE . Strategies to extend plasma half-lives of recombinant antibodies . BioDrugs . 23 . 2 . 93–109 . 2009-04-01 . 19489651 . 10.2165/00063030-200923020-00003 . 12722160 .
  27. Kontermann RE . Strategies for extended serum half-life of protein therapeutics . Current Opinion in Biotechnology . 22 . 6 . 868–76 . December 2011 . 21862310 . 10.1016/j.copbio.2011.06.012 . 22/6 Chemical biotechnology and Pharmaceutical biotechnology .
  28. van Witteloostuijn SB, Pedersen SL, Jensen KJ . Half-Life Extension of Biopharmaceuticals using Chemical Methods: Alternatives to PEGylation . ChemMedChem . 11 . 22 . 2474–2495 . November 2016 . 27775236 . 10.1002/cmdc.201600374 . 205649390 . free .
  29. Makovitzki A, Baram J, Shai Y . Antimicrobial lipopolypeptides composed of palmitoyl Di- and tricationic peptides: in vitro and in vivo activities, self-assembly to nanostructures, and a plausible mode of action . Biochemistry . 47 . 40 . 10630–6 . October 2008 . 18783248 . 10.1021/bi8011675 .
  30. Epand. Richard M.. 1997. Biophysical studies of lipopeptide-membrane interactions . Peptide Science. en. 43. 1. 15–24. 10.1002/(SICI)1097-0282(1997)43:1<15::AID-BIP3>3.0.CO;2-3. 9174409. 1097-0282.
  31. Bulaj. L. Zhang and G.. 2012-03-31 . 22376031 . Converting Peptides into Drug Leads by Lipidation. 2021-01-20. Current Medicinal Chemistry. 19. 11. 1602–1618. en. 10.2174/092986712799945003.
  32. Knudsen LB, Nielsen PF, Huusfeldt PO, Johansen NL, Madsen K, Pedersen FZ, Thøgersen H, Wilken M, Agersø H . 6 . Potent derivatives of glucagon-like peptide-1 with pharmacokinetic properties suitable for once daily administration . Journal of Medicinal Chemistry . 43 . 9 . 1664–9 . May 2000 . 10794683 . 10.1021/jm9909645 .
  33. Pan CQ, Buxton JM, Yung SL, Tom I, Yang L, Chen H, MacDougall M, Bell A, Claus TH, Clairmont KB, Whelan JP . 6 . Design of a long acting peptide functioning as both a glucagon-like peptide-1 receptor agonist and a glucagon receptor antagonist . English . The Journal of Biological Chemistry . 281 . 18 . 12506–15 . May 2006 . 16505481 . 10.1074/jbc.M600127200 . free .
  34. Thorens B . Expression cloning of the pancreatic beta cell receptor for the gluco-incretin hormone glucagon-like peptide 1 . Proceedings of the National Academy of Sciences of the United States of America . 89 . 18 . 8641–5 . September 1992 . 1326760 . 49976 . 10.1073/pnas.89.18.8641 . 1992PNAS...89.8641T . free .
  35. Book: Implantable technologies: peptides and small molecules drug delivery . 2022 . Royal Society of Chemistry . 978-1-83916-222-0 . Srivastava . Ved . Drug development and pharmaceutical science . Cambridge.
  36. Book: Peptide-based drug discovery: challenges and new therapeutics . 2017 . Royal Society of Chemistry . 978-1-78262-732-6 . Srivastava . Ved . Drug discovery series . London . 974673515 . Royal Society of Chemistry (Great Britain).
  37. Book: Peptide therapeutics: strategy and tactics for chemistry, manufacturing, and controls . 2019 . Royal Society of Chemistry . 978-1-78801-433-5 . Srivastava . Ved . Drug discovery series . Cambridge.
  38. Book: Peptide therapeutics: strategy and tactics for chemistry, manufacturing, and controls . 2019 . Royal Society of Chemistry . 978-1-78801-433-5 . Srivastava . Ved . Drug discovery series . Cambridge.
  39. Book: Peptides 2015: proceedings of the Twenty-Fourth American Peptide Symposium, June 20-25, 2015, Orlando, FL, U.S.A . 2015 . Prompt Scientific Publishing . 978-0-9839741-5-4 . Srivastava . Ved . San Diego, U.S.A . Yudin . Andrei . Lebl . Michael . American Peptide Society.
  40. Book: Implantable technologies: peptides and small molecules drug delivery . 2022 . Royal Society of Chemistry . 978-1-83916-222-0 . Srivastava . Ved . Drug development and pharmaceutical science . Cambridge.
  41. Book: Peptide-based drug discovery: challenges and new therapeutics . 2017 . Royal Society of Chemistry . 978-1-78262-732-6 . Srivastava . Ved . Drug discovery series . London . 974673515 . Royal Society of Chemistry (Great Britain).
  42. Book: CNS, pain, metabolic syndrome, cardiovascular, tissue fibrosis and urinary incontinence . 2017 . Elsevier . 978-0-08-102246-7 . Hall . Adrian . 3rd . Comprehensive Medicinal Chemistry III / Samuel Chackalamannil . Amsterdam Oxford Cambridge . Neelamkavil . Santhosh . Jones . Rob.

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