Naturally Occurring Histone Deacetylase (HDAC) Inhibitors in the Treatment of Cancers
Namrita Lall in Medicinal Plants for Cosmetics, Health and Diseases, 2022
Cyclic peptides, also referred as ‘macrocyclic’ compounds, inhibit HDAC by interacting with the outer rim of the enzyme (Mwakwari et al., 2010). These cyclic compounds usually contain complex cap-groups which bind to the HDAC’s outer rim regions, thereby inhibiting the enzyme activity with more potency and isoform selectivity (Maolanon et al., 2016). Based on their macrocyclic moieties, these HDACi are subdivided into: (a) cyclic peptides; and (b) depsipeptides. The first class contains a mixture of L- and D-amino acids and cyclic amino acids such as proline or pipecolic acid (Mwakwari et al., 2010). Examples of cyclic peptides are trapoxin-A and trapoxin-B, apicidin (a fungal metabolite from fusarium species), azumamide (isolated from Mycale izuensis) and HC-toxin (Mwakwari et al., 2010).
Melanotropin Receptors and Signal Transduction
Mac E. Hadley in The Melanotropic Peptides, 2018
Peptide hormones are physiologically active molecules important in a variety of endocrine, neuroregulatory, and other cellular processes. Structurally, linear and cyclic peptides are composed of an ordered, covalent sequence of amino acids which ultimately defines specific topological and, in a few well-studied examples, conformational features essential to their molecular action.16 Functionally, the biological activity of many peptide hormones on their target cells has been shown to involve interaction with a plasma-membrane-localized, complex regulatory enzyme system including: (1) high-affinity, hormone-specific receptors; (2) guanyl nucleotide-binding proteins; (3) monovalent and divalent metal-binding proteins; and (4) adenylate cyclase. In addition, the phospholipid milieu of the plasma membrane may also provide a regulatory role in biological signal transduction by coordinating the activities of the functional components of this enzyme system. The molecular basis of such peptide-receptor binding and subsequent signal transduction processes are elaborated further in Table
Non-FDG radionuclide imaging and targeted therapies
Anju Sahdev, Sarah J. Vinnicombe in Husband & Reznek's Imaging in Oncology, 2020
This receptor system has been implicated in the molecular mechanisms that favour development of metastases. Expression of this receptor in cancer cells favours homing to tissues that express its natural ligand, stromal derived factor 1 (SDF-1), also known as CXCL12. Small peptides targeting CXCR4 were originally developed in the late 1990s (45). Derivatives of the T140 peptide were initially modified for radiolabelling in order to obtain CXCR4-targeting radiopharmaceuticals. Biodistribution properties of these first-generation compounds proved to be unsuitable for successful application. In the early 2000s a small cyclic peptide with more favourable biodistribution properties was identified (46). This compound (GPCR04) has been utilized in preliminary clinical studies in patients with myeloma (47), glioblastoma (48), and lung cancer (49). As CXCR4 is a potential therapeutic target, the main role of these diagnostic agents in the clinic is to establish and quantify receptor expression in tumours. There is also initial clinical experience on targeting CXCR4 expression for radionuclide therapy (50,51).
Strategies for targeting undruggable targets
Published in Expert Opinion on Drug Discovery, 2022
Gong Zhang, Juan Zhang, Yuting Gao, Yangfeng Li, Yizhou Li
Peptide motif participates naturally in PPI. However, the truncated linear peptide does not necessarily fold correctly, losing conformational stability and bioactivity. Therefore, a panel of strategies to stabilize peptide conformation and reduce proteolysis susceptibility have been developed. For α-helix motifs, the staple peptide is an efficient therapeutic entity to facilitate the folding of secondary structures[32]. The cyclic peptide is another classical form of entity, especially for stretched or coiled peptides without well-defined secondary structures[33]. Altogether, the linear/cyclic/staple modes represent diverse peptide conformations adopted to deal with undruggable targets (Figure 1c). Peptidomimetics/proteomimetics represent another category of peptide-derived drugs generated by rational design, display technologies, or library screening. They may contain unnatural amino acid building blocks and cyclic structures, providing advantages over native peptides in aspects of pharmacological property and chemical diversity. Peptidomimetics have been developed to target suppressor of cytokine signaling (SOSC) in the treatment of atherosclerosis and inflammation [34,35].
RGD peptide-based non-viral gene delivery vectors targeting integrin αvβ3 for cancer therapy
Published in Journal of Drug Targeting, 2019
Shuang Fu, Xiaodong Xu, Yu Ma, Shubiao Zhang, Shufen Zhang
The ultimate efficacy of RGD will be likely influenced by many factors, such as steric conformation, direct interaction between additional flanking groups, their receptors and so on [27,28]. Many different RGD-containing peptides with variable structures and flanking amino acids have been examined for a better understanding of RGD activity in vitro and in vivo. The identity of flanking sequence is known to alter both the adhesive strength of RGD as well as selectivity for distinct integrin heterodimers [29–35]. In fact, the cyclisation which confers rigidity to the structure is commonly employed to improve the binding properties of RGD peptide. Furthermore, linear RGD peptide was proved highly susceptible to chemical degradation, which is due to the reaction of the aspartic acid residue (D) with the peptide backbone [36]. Since the rigidity conferred by cyclisation prevents chemical degradation, cyclic peptides are more stable, more potent and more specific. The RGD peptide sequence is flanked by other amino acids in cyclic peptide to build a ring system. These systems offer the possibility to present the RGD sequence in a specific conformation for a selected integrin [28].
Bioactive cyclic molecules and drug design
Published in Expert Opinion on Drug Discovery, 2018
Research in the latter part of the 20th century identified many classes of natural products with a majority being classified into one of four major groups from their structures and biosynthetic mechanisms. These were the terpenoids, alkaloids, polyketides, and non-ribosomal peptides (the NRPs). Although there is not enough space to show many clinically important cyclic peptides, one immunosuppressive agent should be commented on, cyclosporin (aka ciclosporin) shown in Figure 56. The structure of the compound was first reported as an iodo derivative (X-ray) in 1976 [15] and more than 30 variations have been isolated from submerged cultures of T. inflatum all synthesized by the same three enzymes with their genes being organized in a large secondary metabolite cluster. Cyclosporins have been isolated from at least 17 different fungal taxa[16], and all have the necessary ‘flexability’ to cross cell membranes and to interact with peptidyl prolyl cis/trans isomerase. Since the molecule contains D-alanine as well as two other non-proteinogenic amino acids, a D-alanine racemase is part of the genetic cluster, but will also racemize serine, Abu and leucine. The final assembly utilizes a large (15K aminoacid) NRPS complex known as CySyn, which starts with the D-Ala precursor and then follows along with the other 10 aminoacids, followed by cyclization. D-Ala in the cyclic compound is probably a method of stopping proteolytic cleavage of the active molecule.
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