Cyclic Peptides in Neurological Disorders: The Case of Cyclo(His-Pro)

Bellezza, Ilaria; Peirce, Matthew J.; Minelli, Alba

doi:10.1016/b978-0-12-814905-8.00010-1

Cited by 11 publications

(10 citation statements)

References 199 publications

(191 reference statements)

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“…When the common point of these actions was analyzed, dopaminergic mechanisms were found to be the main player of these systems. It was reported that the increase of CHP-like compounds in CSF can improve cognitive function and can enhance neurological recovery after trauma [69]. The cHP4 was determined as the most effective isomer among cHP1-4.…”

Section: Discussionmentioning

confidence: 95%

Histidyl-Proline Diketopiperazine Isomers as Multipotent Anti-Alzheimer Drug Candidates

et al. 2020

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Cyclic dipeptides administered by both parenteral and oral routes are suggested as promising candidates for the treatment of neurodegeneration-related pathologies. In this study, we tested Cyclo (His-Pro) isomers (cHP1-4) for their anti-Alzheimer potential using a differentiated human neuroblastoma cell line (SH-SY5Y) as an Alzheimer’s disease (AD) experimental model. The SH-SY5Y cell line was differentiated by the application of all-trans retinoic acid (RA) to obtain mature neuron-like cells. Amyloid-beta 1-42 (Aβ1-42) peptides, the main effector in AD, were administered to the differentiated cell cultures to constitute the in vitro disease model. Next, we performed cell viability analyses 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) release assays) to investigate the neuroprotective concentrations of cyclodipeptides using the in vitro AD model. We evaluated acetylcholinesterase (AChE), α- and β-secretase activities (TACE and BACE1), antioxidant potency, and apoptotic/necrotic properties and performed global gene expression analysis to understand the main mechanism behind the neuroprotective features of cHP1-4. Moreover, we conducted sister chromatid exchange (SCE), micronucleus (MN), and 8-hydroxy-2′-deoxyguanosine (8-OHdG) analyses to evaluate the genotoxic damage potential after applications with cHP1-4 on cultured human lymphocytes. Our results revealed that cHP1-4 isomers provide a different degree of neuroprotection against Aβ1-42-induced cell death on the in vitro AD model. The applications with cHP1-4 isomers altered the activity of AChE but not the activity of TACE and BACE1. Our analysis indicated that the cHP1-4 increased the total antioxidant capacity without altering total oxidative status levels in the cellular AD model and that cHP1-4 modulated the alterations of gene expressions by Aβ1-42 exposure. We also observed that cHP1-4 exhibited noncytotoxic and non-genotoxic features in cultured human whole blood cells. In conclusion, cHP1-4 isomers, especially cHP4, have been explored as novel promising therapeutics against AD.

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Section: Discussionmentioning

confidence: 95%

Histidyl-Proline Diketopiperazine Isomers as Multipotent Anti-Alzheimer Drug Candidates

et al. 2020

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“…The first example is cyclo(Leu-Gly), the cyclic analog of H-Pro-Leu-Gly-NH2, the C-terminal neurohypophyseal tripeptide of oxytocin, reducing the blockade of memory induced by puromycin, a protein synthesis inhibiting drug which can impair memory processes. The second example is cyclo(Pro-Gly) that was found to reduce motor neuron death induced by glutamate, probably due to the presence of neuroprotective Gly in the structure and potentially slowing down the progression of ALS [181].…”

Section: Other Dkpsmentioning

confidence: 99%

“…It can be derived from glycine-proline-glutamate. It has anxiolytic activity [181]. It is an endogenous prototype of Piracetam (derivative of gamma-aminobutyric acid), a nootropic drug.…”

Section: Other Dkpsmentioning

confidence: 99%

“…Interestingly, DKPs can play a role of PAF inhibitors useful in the treatment of all these dysfunctions [32,294]. More specifically, cyclo(His-Pro), the same as cyclo(Pro-Gly), cyclo(Pro-Ala), cyclo(Pro-Ile), cyclo(Pro-Leu), cyclo(Pro-Ser), cyclo(Pro-Glu), cyclo(Pro-Gln), cyclo(Pro-Cys), cyclo(Pro-Met), cyclo(Pro-Phe), cyclo(Pro-Trp), cyclo(Pro-Tyr), cyclo(Leu-Pro), cyclo(Val-Pro), cyclo(Leu-hydroxy-Pro), and cyclo(Gly-Pro) are a good example of anti-inflammatory agents [74,179,181,[295][296][297]. The latter also has anti-nociceptive effect [298], while cyclo(Leu-Pro) has anti-stress, cytoprotective and genoprotective properties, apart from antimicrobial, antifouling, antimutagenic, carcinogenic activities [299].…”

Section: Pde-5 Inhibitorsmentioning

confidence: 99%

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Cyclic Dipeptides: The Biological and Structural Landscape with Special Focus on the Anti-Cancer Proline-Based Scaffold

et al. 2021

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Cyclic dipeptides, also know as diketopiperazines (DKP), the simplest cyclic forms of peptides widespread in nature, are unsurpassed in their structural and bio-functional diversity. DKPs, especially those containing proline, due to their unique features such as, inter alia, extra-rigid conformation, high resistance to enzyme degradation, increased cell permeability, and expandable ability to bind a diverse of targets with better affinity, have emerged in the last years as biologically pre-validated platforms for the drug discovery. Recent advances have revealed their enormous potential in the development of next-generation theranostics, smart delivery systems, and biomaterials. Here, we present an updated review on the biological and structural profile of these appealing biomolecules, with a particular emphasis on those with anticancer properties, since cancers are the main cause of death all over the world. Additionally, we provide a consideration on supramolecular structuring and synthons, based on the proline-based DKP privileged scaffold, for inspiration in the design of compound libraries in search of ideal ligands, innovative self-assembled nanomaterials, and bio-functional architectures.

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“…[23][24][25] On the other hand, cyclo(His-Pro) is endogenous to the human body as a byproduct of the thyrotropin-releasing hormone. 26,27 It has been proposed as a neuroprotective peptide against Parkinson disease and amyotrophic lateral sclerosis, 28,29 as well as a molecule involved in the gut-brain-axis crosstalk, 30 with effects on glucose metabolism. 31 Thus, it would be advantageous to expand the chemical space of analogues we could produce by using enzymes such as CDPSs.…”

Section: Introductionmentioning

confidence: 99%

Structural-based engineering expands the substrate scope of a cyclodipeptide synthase

Sutherland

Harding

Czekster

2021

Preprint

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Cyclodipeptide synthases (CDPSs) are a growing family of enzymes capable of producing a large variety of cyclodipetide products using aminoacylated tRNA. Histidine-containing cyclic dipeptides have important biological activities as anticancer and neuroprotective molecules. Out of the 120 experimentally validated CDPS members, only two are known to accept histidine as a substrate. Here, we studied the activities of both Para-CDPS from Parabacteroides sp. 20_3 and Parcu-CDPS from Parcubacteria bacterium RAAC4_OD1_1 which synthesise cyclo(His-Phe) and cyclo(His-Pro) respectively. Both enzymes accepted canonical and non-canonical amino acids as substrates to generate a library of novel molecules. In order to understand the substrate selectivity of these CDPSs, the crystal structure of Parcu-CDPS was solved (alongside a number of mutants) and the role of residues important for catalysis and histidine recognition were probed using mutagenesis. Three successive generations of mutants containing both single and double residue substitutions were generated leading to a change in substrate selectivity from histidine to phenylalanine and leucine. The research detailed herein is the first instance of successful engineering of a CDPS to yield different products, paving the way to direct the promiscuity of these enzymes to produce molecules of our choosing.

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Cyclic Peptides in Neurological Disorders: The Case of Cyclo(His-Pro)

Cited by 11 publications

References 199 publications

Histidyl-Proline Diketopiperazine Isomers as Multipotent Anti-Alzheimer Drug Candidates

Histidyl-Proline Diketopiperazine Isomers as Multipotent Anti-Alzheimer Drug Candidates

Cyclic Dipeptides: The Biological and Structural Landscape with Special Focus on the Anti-Cancer Proline-Based Scaffold

Structural-based engineering expands the substrate scope of a cyclodipeptide synthase

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