Peptide therapeutics

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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]

Contents

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. [8] 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. [18]

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. [14]

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]

Related Research Articles

<span class="mw-page-title-main">Post-translational modification</span> Chemical changes in proteins following their translation from mRNA

In molecular biology, post-translational modification (PTM) is the covalent process of changing proteins following protein biosynthesis. PTMs may involve enzymes or occur spontaneously. Proteins are created by ribosomes, which translate mRNA into polypeptide chains, which may then change to form the mature protein product. PTMs are important components in cell signalling, as for example when prohormones are converted to hormones.

<span class="mw-page-title-main">Glycoprotein</span> Protein with oligosaccharide modifications

Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. Secreted extracellular proteins are often glycosylated.

<span class="mw-page-title-main">Glucagon</span> Peptide hormone

Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises the concentration of glucose and fatty acids in the bloodstream and is considered to be the main catabolic hormone of the body. It is also used as a medication to treat a number of health conditions. Its effect is opposite to that of insulin, which lowers extracellular glucose. It is produced from proglucagon, encoded by the GCG gene.

<span class="mw-page-title-main">Lipolysis</span> Metabolism involving breakdown of lipids

Lipolysis is the metabolic pathway through which lipid triglycerides are hydrolyzed into a glycerol and free fatty acids. It is used to mobilize stored energy during fasting or exercise, and usually occurs in fat adipocytes. The most important regulatory hormone in lipolysis is insulin; lipolysis can only occur when insulin action falls to low levels, as occurs during fasting. Other hormones that affect lipolysis include leptin, glucagon, epinephrine, norepinephrine, growth hormone, atrial natriuretic peptide, brain natriuretic peptide, and cortisol.

<span class="mw-page-title-main">Index of biochemistry articles</span>

Biochemistry is the study of the chemical processes in living organisms. It deals with the structure and function of cellular components such as proteins, carbohydrates, lipids, nucleic acids and other biomolecules.

Glycosylation is the reaction in which a carbohydrate, i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule in order to form a glycoconjugate. In biology, glycosylation usually refers to an enzyme-catalysed reaction, whereas glycation may refer to a non-enzymatic reaction.

An oligosaccharide is a saccharide polymer containing a small number of monosaccharides. Oligosaccharides can have many functions including cell recognition and cell adhesion.

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<span class="mw-page-title-main">Serum albumin</span> Type of globular protein produced by the liver

Serum albumin, often referred to simply as blood albumin, is an albumin found in vertebrate blood. Human serum albumin is encoded by the ALB gene. Other mammalian forms, such as bovine serum albumin, are chemically similar.

<span class="mw-page-title-main">Sex hormone-binding globulin</span> Human glycoprotein that binds to androgens and estrogens

Sex hormone-binding globulin (SHBG) or sex steroid-binding globulin (SSBG) is a glycoprotein that binds to androgens and estrogens. When produced by the Sertoli cells in the seminiferous tubules of the testis, it is called androgen-binding protein (ABP).

<span class="mw-page-title-main">Human serum albumin</span> Albumin found in human blood

Human serum albumin is the serum albumin found in human blood. It is the most abundant protein in human blood plasma; it constitutes about half of serum protein. It is produced in the liver. It is soluble in water, and it is monomeric.

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Melanocortin receptors are members of the rhodopsin family of 7-transmembrane G protein-coupled receptors.

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<span class="mw-page-title-main">PEGylation</span> Chemical reaction

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<span class="mw-page-title-main">Protein–ligand complex</span>

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<span class="mw-page-title-main">Polymer-protein hybrid</span> Nanostructures of protein-polymer conjugates

Polymer-protein hybrids are a class of nanostructure composed of protein-polymer conjugates. The protein component generally gives the advantages of biocompatibility and biodegradability, as many proteins are produced naturally by the body and are therefore well tolerated and metabolized. Although proteins are used as targeted therapy drugs, the main limitations—the lack of stability and insufficient circulation times still remain. Therefore, protein-polymer conjugates have been investigated to further enhance pharmacologic behavior and stability. By adjusting the chemical structure of the protein-polymer conjugates, polymer-protein particles with unique structures and functions, such as stimulus responsiveness, enrichment in specific tissue types, and enzyme activity, can be synthesized. Polymer-protein particles have been the focus of much research recently because they possess potential uses including bioseparations, imaging, biosensing, gene and drug delivery.

Lysozyme PEGylation is the covalent attachment of Polyethylene glycol (PEG) to Lysozyme, which is one of the most widely investigated PEGylated proteins.

References

Creative Commons by-sa small.svg  This article incorporates text by Jessica Hutchinson available under the CC BY-SA 3.0 license.

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