The Renin-Angiotensin System
Austin E. Doyle, Frederick A. O. Mendelsohn, Trefor O. Morgan in Pharmacological and Therapeutic Aspects of Hypertension, 2020
A range of synthetic peptides containing the sequence Leu-Leu were found to be inhibitors of the reaction of rabbit renin and substrate.606,607 Those peptides which were active had Leu-Leu at the amino-terminus, the amino-terminal Leu was in the L configuration, and Tyr or Phe occurred at the C-terminus. Examples of active inhibitors were the methyl or ethyl esters of Leu-Leu-Val-Tyr or Leu-Leu-Val-Phe. These compounds were competitive inhibitors producing 50% inhibition of renin at approximately 2 mg/mℓ and were of comparable activity to the octapeptide, Pro-Phe-His-Leu-Val-Tyr-Ser. The methyl esters of these two tetrapeptides (Leu-Leu-Val-Tyr-Och3 and Leu-Leu-Val-Phe-OCH3) and the tripeptide (Leu-Leu-Val-OCH3) were found to be inhibitors of the reaction od hog renin with a synthetic 3H-labeled tetradecapeptide substrate, of human renin with the synthetic substrate, and of human renin with plasma substrate.38 The tetrapeptides were more active than the tripeptide, and all were more effective in inhibiting the action of human rather than hog renin acting on the synthetic substrate (Table 6). The tetrapeptide, Leu-Leu-Val-Tyr-OCH3, was shown to be a classical competitive inhibitor, but was not cleaved by renin.
Melanotropin Mechanisms of Action: Melanosome Movements
Mac E. Hadley in The Melanotropic Peptides, 2018
Several fragment analogs of MCH have been synthesized and characterized for melanotropic activity: MCH1-14, MSH5-17, and MCH5-14.38 Structure-activity studies have determined that the 5-17 sequence was as active as the native peptide, suggesting that the N-terminal tetrapeptide sequence may be of no importance for receptor activation. The 1-14 sequence was approximately 30 times less active than the native 1-17 sequence, and the central cyclic 5-14 sequence proved to be approximately 300 times less active. One or more residues of the 15-17 sequence are apparently essential for equipotency at the MCH receptor. At higher, unphysiological concentrations, MCH exhibited a self-antagonism, an autoinhibition.39 It was hypothesized that the peptide possessed some intrinsic MSH-like activity and that MCH and MSH might be evolutionarily related (see Sherbrooke et al., Volume II, Chapter 12).
Stimulus-Secretion Coupling: Receptors
Stephen W. Carmichael, Susan L. Stoddard in The Adrenal Medulla 1986 - 1988, 2017
Nieber, Oehme, Arefolov et al. (1988) noted that two structurally related tetrapeptides, the amino-terminal tetrapeptide of substance P and tuftsin, had some similarities in modifying immune reactions and normalizing stress-induced disorders in the adrenal medulla. Both peptides inhibited nicotine-evoked catecholamine outflow, the substance P-derived peptide being more effective. The substance P-derived peptide also inhibited the electrically stimulated release of acetylcholine whereas tuftsin did not. It was suggested that the regulation of the cholinergic-adrenergic interaction in adrenals is mediated by specific receptors that are different on the presynaptic and postsynaptic sides.
Discovery of dual S-RBD/NRP1-targeting peptides: structure-based virtual screening, synthesis, biological evaluation, and molecular dynamics simulation studies
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Chunfang Hu, Ting Guo, Yunting Zou, Junyi Gao, Yi Gao, Miaomiao Niu, Yang Xia, Xiaozhou Shen, Jindong Li
The crystal structure of the b1 domain of NRP1 (NRP1-BD) was obtained from PDB (PDB ID: 7JJC) and preprocessed via Prepare Protein tool. The virtual library containing 24 000 peptides was self-constructed using the QuaSAR-CombiGen module of MOE. This module created a random peptide by linking nonapeptide fragments, heptapeptide fragments, dodecapeptide fragments, and tetrapeptide fragments; see the reported article for more details34. The converting of each peptide structure from 2D to 3D was achieved by the use of the Energy Minimisation algorithm. Based on the generated pharmacophore model of S-RBD, a pharmacophore-based docking simulation was conducted to identify S-RBD-targeting peptides by the Docking module of MOE. Key residues on the binding surface of S-RBD were selected as a binding site. The pharmacophore-base docking algorithm served to dock peptides into the S-RBD binding site. The binding free energy was calculated by the dG docking scoring. The selected peptides with docking scores lower than −13.5 kcal/mol subsequently docked into the NRP1-BD active site with the triangle matcher algorithm. Finally, according to the dG docking scores, the top five peptides were selected for in vitro biological testing.
Advances in molecular therapies for targeting pathophysiology in spinal cord injury
Published in Expert Opinion on Therapeutic Targets, 2023
Ha Neui Kim, Madeline R. McCrea, Shuxin Li
Local injection of peptide amphiphile supramolecular polymers into lesioned spinal cord could stimulate remarkable vascular growth, axonal regeneration, myelination, survival of motor neurons, reduced gliosis, and functional recovery [109]. This study reported the new synthetic nanoscale polymers that contain peptides to activate integrin β-1 and basic FGF2 receptors. These biomaterials preserve biological signals of two receptors at the same extent but slightly mutate the tetrapeptide sequence of targeted domains, thus exhibiting great therapeutic potential for severe CNS injury. Treatments with epothilones, the natural compounds that could stabilize microtubules, increased axon regrowth and locomotor recovery of hindlimbs in SCI rats, and a combination of epothilone B with rehabilitation showed complementary effects on functional recovery [110].
A mitochondrial-targeted peptide ameliorated podocyte apoptosis through a HOCl-alb-enhanced and mitochondria-dependent signalling pathway in diabetic rats and in vitro
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Xiaoqiao Wang, Dongdong Tang, Yaowei Zou, Xiaoyu Wu, Yihua Chen, Hongying Li, Siqi Chen, Yue Shi, Hongxin Niu
General antioxidants, such as vitamin E, β-carotene, and vitamin A, have been shown to have no obvious benefits in reducing DM complications13,14, inferring that these compounds might be distributed in the cytoplasm or extracellularly, could not enter the mitochondria, and had difficulty in exerting antioxidant effects. A new type of cell-permeable tetrapeptide was initially designed and synthesised by Szeto and Schiller and named the SS peptides. Among these peptides, SS-31 was reported to target and accumulate in the inner membrane of mitochondria and scavenge mtROS, thereby preventing mitochondrial depolarisation, mitochondrial permeability transition, and cytochrome c (cyt c) release from mitochondria to cytoplasm15. The SS peptide protects N2A neuroblastoma cells, Caco-2 colon cancer cells16, HLEB-3 human lens epithelial cells17, NRK52E rat renal tubular cells18, and mouse mesangial cells19 from death. However, the roles and mechanisms of the SS peptide in podocytes under the circumstances of DM and oxidative stress remain largely unknown.
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