Peptides for healing in the wound healing pathway of the body. The first part of the paper covers the historical perspective of the peptide research and introduces the different types of peptides currently in development or use in the market place.
The discovery of hormones by Harvey in the beginning of the 17th century was an important milestone in the development of physiology and medicine. However the hormone concept as we know it today only emerged in the 20th century. It was with the discovery of insulin and glucagon by Wollman in 1921. In the same decade that Jolles and Eisenberg described the effect of hormones on target organs and formulated the concept of hormone action in the first place. By the end of the 1930s, the concept of an endocrine gland as a source of a particular hormone, the parathyroid, was introduced. The endocrine glands are a heterogeneous group of glands from which different kinds of hormones are produced.
What are Endocrine Glands?
These are synthesized and released into the blood circulation or into the extracellular fluid (e.g., renin, pituitary hormones, hormones of the thyroid, and ovary). The endocrine gland hormones are either transported by the blood circulation. They are carried by the lymphatics and are stored in specialized cells in endocrine glands. In spite of such a simple definition, there has been much confusion about whether one hormone could be formed from another hormone. A classic example of this is the hormone oxytocin that was shown in 1955 to be formed from a glycoprotein synthesized in the pituitary.
In addition to the endocrine gland hormones, there are also local autocrine or paracrine hormones which are synthesized by a gland. These are secreted into the local tissue, and act on other cell type present in that tissue. Some hormones are produced by organs other than the endocrine glands such as the insulin, glucagon, and growth hormone produced by the pancreas, thyroid, liver, and by tumors of the pituitary and gastrointestinal tracts. These tissues and organs are known as target organs. The target organs can also be considered as endocrine glands, and the target organ hormone can be considered as an autocrine hormone. A paracrine hormone is produced by a hormone producing cell and is secreted into the local tissue and acts on the target cell itself. A combination of these types of hormone exists in many cases.
The Development of HRT
The identification of hormones, their specific target cells, mode of action and synthesis was facilitated by a better understanding of the anatomy of endocrine glands and the target organs. The development of endocrinology as a medical specialty led to the first clinical hormone replacement therapies. Today, the pharmaceutical industry has developed and produced huge amounts of synthetic hormones that were either isolated from the endocrine glands or were synthesized in the laboratory. A second wave of synthetic hormones and analogues is being generated and marketed for a wide range of diseases. Some of these are peptides and the paper will focus on these new peptides and the challenges facing this field.
Chemistry of the Peptides
Over 100 peptide hormones have been described and many more have been purified and sequenced to provide basic information on the structure and the metabolism of hormones. These have been published as reviews in various recent textbooks. The structural complexity of the peptide hormones is illustrated by a series of molecular biology studies of the insulin-like growth factors in which the insulin and transforming growth factor-beta precursor proteins were shown to be cleaved to smaller peptides. There is a family of insulin-like growth factors including IGF-I, IGF-II, insulin-like growth factor binding protein-1, and IGF binding protein-2. Of the 6 major IGF molecules, IGF-I has the most homology to the proinsulin molecule and the other peptides are thought to be derived from IGF-I by exo-proteolysis of the peptide bond in the C-terminus of the A-chain and B-chain.
A Guide to Amino Acids
The amino acid sequence of the peptides that form hormones can be determined from the isolation of the hormone from the tissue and from the molecular cloning of its DNA sequence. Knowledge of the primary structure of a hormone is needed for further biochemical, structural, and functional analysis. The structure of the intact hormone is only a small part of the structural information available for the peptide. Knowledge of the amino acid sequence and the structural modifications of the peptide has led to the development of analogues of the hormone that could have better activity, be less expensive to produce, and have less side effects.
Studies with Amino Acids
Such studies involve modifying the amino acids in the primary structure of the peptides and by amino acid replacement. Other approaches to modify the hormone are the insertion of amino acids in the primary structure of the peptide. It produces modified analogues and the chemical synthesis of analogues by modifying the side chain of the amino acids and/or the addition of peptide bonds to the molecule.
The amino acid sequence of a hormone is used to predict its three-dimensional structure. By this method, all the structural and dynamical studies of hormones have been made. The results of the X-ray crystallography of the hormone and model peptides suggest that these molecules can assume different shapes in solution. In the absence of 3D structure in a protein, the sequence of the peptide, the primary structure, is sufficient for an understanding of the structure and functions of the molecule. It is an important aspect of peptide structure-function studies.
By determining the peptide’s primary structure and the amino acid sequence of the peptide hormone, it is possible to design analogues by a rational design approach. Especially where the molecule is constructed in silico and tested in silico. The development of peptide based drugs that function in living cells is a challenge. The development of peptides as therapeutics is also a challenge because of the high level of specificity required of the biological system.
Biochemistry of the Peptides
The biological function of peptide hormones is controlled by a series of proteins that control the release, transport, and breakdown of the hormones. These proteins act as transporters, enzymes, and storage proteins. The biological function of the peptide hormone requires that the peptide hormone be released from the secretory system into the blood stream or lymph. The transport of the peptide hormone in the blood can be regulated by enzymes and carrier proteins. There are mechanisms that control the binding and interaction of the hormone with its receptor.
How Peptides Work?
The receptor is a membrane protein that has an extracellular domain, an intracellular domain, and a transmembrane domain. Once the peptide is released into the blood stream, the receptor may bind and activate a second protein that initiates the signal cascade that regulates the biological function of the hormone. Once the signal is initiated, there is the process of desensitization. Desensitization occurs if a particular receptor is activated repeatedly. In addition, there is the process of receptor downregulation which involves the internalization of the receptor as well as a decrease in the number of functional receptors. A major effort in biochemistry is the understanding of the mechanism of receptor downregulation. The downregulation of receptors, is of interest to those who want to maintain the bioactivity of the receptor and the signaling pathway of the receptor.
Once the signaling pathway is initiated, the activation of the pathway needs to be regulated by other proteins which control the activation, desensitization, internalization, and degradation of the signaling pathway and the proteins of the receptor. Some hormones bind and signal in an autocrine manner when a ligand binds to its receptor in the same cell and activates the pathway and then enters another intracellular signaling pathway.
In contrast to the more common signaling pathways in which the receptor binds a peptide hormone which has been secreted and is circulating in the blood. A third type of receptor signaling pathway that has been discovered is the paracrine signaling pathway. It occurs when a ligand binds to the receptor on a cell in one tissue and signals an intracellular process in another cell in another tissue. The signaling pathway may be paracrine and go through the circulation and then the signaling can be initiated in another cell. The blood level of the hormone is one of the regulatory factors of the activation and desensitization of the receptor.
The receptor may be degraded at any point along its pathway. The rate at which the receptor is internalized is of interest to those who control the intracellular pathways. Those who do not understand the mechanisms that regulate the intracellular signaling pathway need to know about the role of the internalization process of the receptor on the duration of the signaling. The mechanism of downregulation will also be an important aspect of receptor research. It has also been found that cells in different tissues of the body have receptors for the same hormone and many of these receptors have a similar structure and are coded by the same gene.
Hormone Receptors and Receptor Families
Hormone receptors are an integral part of the signaling pathway that leads to activation of the biological function of a peptide hormone. Although the peptide hormone, hormone analogue, and receptor are different from the biochemical point of view, they are linked to one another through a series of proteins in the pathway. The peptide hormone binds to the receptor and is transported into the cell. This is an essential step for the receptor to become activated. When the hormone reaches the cell, there is the docking to the receptor and the internalization of the hormone from the external environment into the cell. The receptor can be recycled back to the external surface or internalized by endocytosis, depending on the ligand.
The Action of Peptide Hormones
There is a specific receptor protein for each peptide hormone. Some receptors can be activated by more than one hormone. It can also be dependent on whether the peptide is released from an exocrine gland or from an endocrine gland. When the peptide is released from a gland, the body makes the signal with the release of a small amount of hormone to control the cellular process. In this case, the process is regulated by the concentration of the peptide hormone in the blood. The release of a peptide hormone may be a regulatory process and not a response to an external stimulus, such as the pituitary releasing trophic hormones which controls the internal secretions of the body.
In other cases, the hormone may be released in the blood in response to the interaction of a hormone with the receptor. The release of the peptide hormone is related to the binding of the peptide to the receptor. This can be an allosteric process where the ligand controls the receptor by increasing the rate of activation of the receptor or deactivating the receptor. In this case, the hormone and its receptor are in a regulatory network. A hormone receptor can be a monomer, dimer, or oligomer which can vary by different amino acids in the sequence. The number of receptor molecules on the cell surface at any point in time may be dependent on the cell type and may be tissue specific. The function of a receptor is to receive the signal from a hormone and transmit the signal to the cellular machinery. The activation of the receptor must also be controlled by mechanisms of receptor down-regulation.
The receptor can be either an agonist receptor or an antagonist receptor. In the case of an agonist receptor, there is a specific response to the hormone and the receptor can bind to the hormone and increase the response of the cell. The receptor can also bind to the hormone, but it does not initiate the cellular response that results from the binding of the agonist to the receptor. It may be more of an antagonist than an agonist. It does not mean that the receptor does not play an important role in the signaling pathway.
How do Peptide Hormones Work?
There may be a number of receptors for the same peptide and this fact is an important consideration when making comparisons of the biological response in different tissues. The same hormone receptor may exist on different types of cells with different effects on the cell. It can also be an important feature to take into consideration when developing a therapeutic agent. The fact that the same ligand can stimulate the function of different receptor types is important to the understanding of the effects of the hormone in the body. Some examples of receptor families include the G-protein coupled receptors, olfactory receptors, and steroid hormone receptors.
Action of Proteins
There are also other proteins that are involved in the functioning of a receptor. A receptor that is regulated by other proteins in the pathway is a receptor that can be modulated by other molecules. If this is the case, the hormone receptor is not only important for its function but for its interaction with other proteins in the pathway. The regulation of the receptor by other proteins and the mechanisms of regulation need to be considered in the design of new therapeutic agents for the hormone of interest. The regulation of the receptor may be by protein kinase-mediated phosphorylation. The activation of receptors can be initiated by other ligands.
The regulation of a receptor by protein kinases provides for the important biological function of a receptor. It has been found that the hormone receptor for a peptide hormone can be regulated by other kinases that phosphorylate the receptor. When the receptor is phosphorylated by a kinase, the function of the receptor is affected and the hormone may also function differently from the receptor. In the case of a receptor that has no functional response when the hormone binds to it, the receptor may have an inhibitory function. A receptor may be activated by another kinase that initiates the signaling pathway. This is possible due to the similarity of the G-protein coupled receptors to the receptors of other receptor families, including the receptor family of cell surface receptors.
The Function of the Hormone
The function of the receptor is important for the understanding of the function of the hormone. The receptor is regulated by other kinases. For example, the insulin receptor and its function is regulated by tyrosine kinases and serine kinases. The serine kinases regulate the function of the receptor by stimulating the function of the receptor to transmit the signal in the signaling pathway. The tyrosine kinases affect the receptor by desensitizing the receptor and the activation of other signaling pathways.
The number of different ligands for each receptor has also been found to have an important role in the function of the receptor. The number of agonists to the receptor can affect the function of the receptor. One receptor can have different types of agonists, such as agonists and antagonists, for the receptor. The receptor may have similar amino acid sequences and a similar three-dimensional structure but one receptor may have many agonists and another may have none. This can affect the biological action of a hormone in the body.
The receptors in some cases may also be activated by endogenous peptides that interact with the receptor. The interaction of a hormone with the receptor is specific and this is determined by the specificity of the amino acid sequence of the hormone.
Interaction of Hormones
It is important to know that the hormone may interact with other receptors and the hormone may activate other receptors. The receptor for the insulin hormone can be activated by the interaction of the hormone with the receptor. In this case, the receptor has a specific binding site for a peptide hormone and another receptor is not activated by the hormone but activated by other peptide hormones. A receptor for the insulin hormone in some cases may be activated by endogenous ligands.
There is evidence for the existence of endogenous peptides that interact with the insulin receptor in some tissues. The receptor may have a specific response to the hormone in addition to the response to the endogenous peptide.
Hormone Receptor Activation and Regulation
The first receptor activated by a hormone is a G-protein coupled receptor and it is a transmembrane protein receptor. The extracellular domain of the receptor interacts with the ligand. In some cases, the G-protein coupled receptor is a receptor that has more than one ligand. There is an intracellular domain of the receptor which is embedded in the plasma membrane and is a membrane-bound protein. This protein is phosphorylated by protein kinases and it activates the signaling pathway to the cell by initiating the intracellular signaling cascade. The G-protein coupled receptor does not have any enzymatic activity and is a receptor which affects the function of the cell by initiating the intracellular signaling pathway. There is also evidence for the existence of receptor proteins which are not transmembrane proteins and these proteins can affect the function of the cell by internalizing into the cell.
The receptor has a cytoplasmic tail which may bind to a cytoplasmic signaling molecule, either a protein or a molecule that contains a chemical group that can transfer to the membrane and initiate intracellular signaling. The cytoplasmic tail also has binding sites for the second messenger, signaling molecules, and other proteins that interact with the intracellular domain of the receptor. In this case, the ligand interacts with the receptor extracellular domain, the intracellular domain of the receptor, and other proteins that interact with the cytoplasmic tail of the receptor.
The interaction of the ligand with the receptor is specific. The interaction of the ligand with the receptor leads to the activation of the receptor. In the case of the receptor which is not a transmembrane protein, it may have a ligand which can activate the receptor and when the ligand activates the receptor, the receptor activates the signaling pathway. The signaling pathway can be divided into different pathways depending on the nature of the receptor. These include the mitogen-activated protein kinase pathway, the nuclear factor kappa-B pathway, the calcium-calmodulin-kinase pathway, and the phosphatidylinositol-3-kinase pathway.
Biological Significance of G-Protein Coupled Receptor Reactivation
The activation of a receptor by the hormone can be controlled by other proteins that interact with the receptor. When a receptor is activated by a hormone, the receptor will initiate the formation of second messengers in the cell. There is an important process of termination of the hormone signaling by proteins that inactivate the receptor. These proteins are called negative regulators. The negative regulators are located on the cell membrane or in the cell. In the case of receptors which are G-protein coupled receptors, there are different negative regulators that can inactivate the receptor.
The inactivation of the receptor is controlled by the phosphorylation of the receptor by protein kinases. In some cases, the receptor may be phosphorylated and activated to transmit the signal to the cell. The inactivation of the receptor occurs when the receptor interacts with the regulatory proteins that will cause the receptor to become dephosphorylated.
The receptor may also be inactivated by other proteins that bind to the receptor. There is an interaction of proteins that activate the receptor with the protein phosphatase. There is a complex signaling pathway that occurs when a receptor is activated. The receptor can be activated by the hormone and be inactivated by other proteins in the pathway. This means that the receptor is inactivated by the interaction of the regulatory proteins in the pathway with other proteins. The proteins that activate the receptor also can inactivate the receptor through the action of the receptor phosphatase.
The formation of the G-protein coupled receptor is also under the control of other molecules in the pathway. The receptor can be inactivated by other regulatory proteins that interact with the receptor and regulate its function. This may be a signaling protein that is activated by another protein in the pathway and the activation of the signaling protein by the other protein in the pathway is a regulatory function that inactivates the receptor. It has been shown that the regulation of the receptor by other proteins that interact with the receptor can be inactivating the receptor.
Signal-Mediated Receptor Activation and Downstream Processing
The hormone binds to the receptor on the cell membrane and the receptor is activated and transmits the hormone signal to the cell. This activates a protein in the cell to transmit the signal through a signaling pathway in the cell. There is an interaction of the protein with other proteins in the pathway. A protein kinase phosphorylates the signaling protein, which causes the protein to have different functional properties. A protein in the pathway is phosphorylated and the signal is transferred. There is an interaction of signaling proteins with other signaling proteins in the cell. The interaction of the proteins with the hormone activates the cell to perform different functions. The signaling proteins interact with different receptor proteins on the cell membrane and other proteins in the cell. This means that there is a complex signaling pathway in the cell which is not completely understood.