This paper describes the synthesis of peptide fragments for use in a new type of combinatorial discovery technology, in which the building blocks are brought together by non-covalent interactions, rather than direct c...This paper describes the synthesis of peptide fragments for use in a new type of combinatorial discovery technology, in which the building blocks are brought together by non-covalent interactions, rather than direct chemical bonding. The building blocks of interest—in this case different amino acids—are converted to amphiphiles by attachment to lipid tails. The amphiphiles, when mixed together in aqueous phase, are designed so that they aggregate spontaneously to form micelles. The building blocks form the headgroups of each of the amphiphiles, and these headgroups cover the surface of the micelle in a dynamic close-packed fluid mosaic array. These building blocks come together so closely that two- or three-dimensional structures are created on the surface of the micelles, and these can be screened in biological assays to find out which combination of building blocks is able to elicit a biological response. Lipopeptides consisting of two residues of lipoamino acid and other amino acids moieties have been designed, synthesized, characterized and the ability of these constructs to form supra-molecular assemblies is demonstrated.展开更多
Luteinizing hormone-releasing hormone (LHRH) is the key regulator of the hypothalamic-pituitary-gonadal (HPG) axis, which is responsible for the development and functioning of the reproductive system. Delivery of a co...Luteinizing hormone-releasing hormone (LHRH) is the key regulator of the hypothalamic-pituitary-gonadal (HPG) axis, which is responsible for the development and functioning of the reproductive system. Delivery of a continuous supply of LHRH agonists causes down-regulation of the LHRH receptors, resulting in a marked decrease in androgens in males and estrogens in females. LHRH analogues are widely used in the treatment of various diseases, including prostate and breast cancer, and reproductive disorders, such as infertility and precocious puberty. However, they require parenteral administration, and no oral formulations are currently available. We synthesized two types of LHRH mini-dendrimers using thioether ligation, aiming to enhance the stability and bioavailability of the peptide drug while maintaining its biologically active conformation. These two compounds include a poly-lysine core conjugated to either the C-terminus of LHRH or a D-amino acid in position 6 of the LHRH sequence. The synthesized dendrimers were analysed using dynamic light scattering, and showed particle sizes of 155 and 115 nm, respectively. The nanometer size, well-defined structure and water solubility of these dendritic analogues make them excellent candidates for further exploration in oral peptide drug delivery.展开更多
Endomorphin-1 is an endogenous opioid peptide that mediates pain relief through interaction with the μ-opioid receptor in the central nervous system. To enhance the metabolic stability of this tetrapeptide, cyclisati...Endomorphin-1 is an endogenous opioid peptide that mediates pain relief through interaction with the μ-opioid receptor in the central nervous system. To enhance the metabolic stability of this tetrapeptide, cyclisation through the formation of a disulfide bridge between the side chains of cysteine residues added to the sequence was explored. A further increase in stability was achieved through N-terminal modification with lipoamino acid and lactose succinamic acid, and the inclusion of D-amino acids. The latter also provided an alternative spatial arrangement of the aromatic side chains. The lipidated cyclic derivatives were insoluble in aqueous buffer, however, the cyclic peptides and glycopeptides showed greatly improved stability towards enzymatic degradation in human plasma.展开更多
文摘This paper describes the synthesis of peptide fragments for use in a new type of combinatorial discovery technology, in which the building blocks are brought together by non-covalent interactions, rather than direct chemical bonding. The building blocks of interest—in this case different amino acids—are converted to amphiphiles by attachment to lipid tails. The amphiphiles, when mixed together in aqueous phase, are designed so that they aggregate spontaneously to form micelles. The building blocks form the headgroups of each of the amphiphiles, and these headgroups cover the surface of the micelle in a dynamic close-packed fluid mosaic array. These building blocks come together so closely that two- or three-dimensional structures are created on the surface of the micelles, and these can be screened in biological assays to find out which combination of building blocks is able to elicit a biological response. Lipopeptides consisting of two residues of lipoamino acid and other amino acids moieties have been designed, synthesized, characterized and the ability of these constructs to form supra-molecular assemblies is demonstrated.
文摘Luteinizing hormone-releasing hormone (LHRH) is the key regulator of the hypothalamic-pituitary-gonadal (HPG) axis, which is responsible for the development and functioning of the reproductive system. Delivery of a continuous supply of LHRH agonists causes down-regulation of the LHRH receptors, resulting in a marked decrease in androgens in males and estrogens in females. LHRH analogues are widely used in the treatment of various diseases, including prostate and breast cancer, and reproductive disorders, such as infertility and precocious puberty. However, they require parenteral administration, and no oral formulations are currently available. We synthesized two types of LHRH mini-dendrimers using thioether ligation, aiming to enhance the stability and bioavailability of the peptide drug while maintaining its biologically active conformation. These two compounds include a poly-lysine core conjugated to either the C-terminus of LHRH or a D-amino acid in position 6 of the LHRH sequence. The synthesized dendrimers were analysed using dynamic light scattering, and showed particle sizes of 155 and 115 nm, respectively. The nanometer size, well-defined structure and water solubility of these dendritic analogues make them excellent candidates for further exploration in oral peptide drug delivery.
文摘Endomorphin-1 is an endogenous opioid peptide that mediates pain relief through interaction with the μ-opioid receptor in the central nervous system. To enhance the metabolic stability of this tetrapeptide, cyclisation through the formation of a disulfide bridge between the side chains of cysteine residues added to the sequence was explored. A further increase in stability was achieved through N-terminal modification with lipoamino acid and lactose succinamic acid, and the inclusion of D-amino acids. The latter also provided an alternative spatial arrangement of the aromatic side chains. The lipidated cyclic derivatives were insoluble in aqueous buffer, however, the cyclic peptides and glycopeptides showed greatly improved stability towards enzymatic degradation in human plasma.
