Development of Macrocyclic Peptidomimetics Containing Constrained α,α-Dialkylated Amino Acids with Potent and Selective Activity at Human Melanocortin Receptors

Merlino, Francesco; Zhou, Yang; Cai, Minying; Carotenuto, Alfonso; Yousif, Ali Munaim; Brancaccio, Diego; Maro, Salvatore Di; Zappavigna, Silvia; Limatola, Antonio; Novellino, Ettore; Grieco, Paolo; Hruby, Victor J.

doi:10.1021/acs.jmedchem.8b00488

Cited by 14 publications

(11 citation statements)

References 38 publications

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“…Peptides D and E were otherwise obtained by the introduction of Orn(Alloc) residue at C-terminal. The ornithine allyl protecting group was removed in orthogonal condition with respect to the Fmoc/ t Bu 32 . Specifically, the resin was treated with a suspension of Pd(PPh 3 ) 4 (0.15 equiv) and 1,3-dimethylbarbituric acid (3 equiv) in DCM/DMF (3:2 v/v ) and gently shaken for 1 h under argon ( Scheme S2, see Supporting Information ).…”

Section: Methodsmentioning

confidence: 99%

Novel temporin L antimicrobial peptides: promoting self-assembling by lipidic tags to tackle superbugs

Bellavita

Falanga

Buommino

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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The rapid development of antimicrobial resistance is pushing the search in the discovering of novel antimicrobial molecules to prevent and treat bacterial infections. Self-assembling antimicrobial peptides, as the lipidated peptides, are a novel and promising class of molecules capable of meeting this need. Based on previous work on Temporin L analogs, several new molecules lipidated at the Nor and the C-terminus were synthesised. Our goal is to improve membrane interactions through finely tuning self-assembly to reduce oligomerisation in aqueous solution and enhance self-assembly in bacterial membranes while reducing toxicity against human cells. The results here reported show that the length of the aliphatic moiety is a key factor to control target cell specificity and the oligomeric state of peptides either in aqueous solution or in a membrane-mimicking environment. The results of this study pave the way for the design of novel molecules with enhanced activities.

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Section: Methodsmentioning

confidence: 99%

Novel temporin L antimicrobial peptides: promoting self-assembling by lipidic tags to tackle superbugs

Bellavita

Falanga

Buommino

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…Fingolimod (FTY720) was purchased from MedChemExpress (Italy, catalog number HY-12005/CS-0114); Ex 26 [1-(5'-((1-(4-chloro-3methylphenyl)ethyl)amino)-2′-fluoro-3,5-dimethyl-[1,1′-biphenyl]-4-ylcarboxamido cyclopropanecarboxylic acid)], a selective S1PR1 antagonist, from Tocris (Italy, catalog number 5833) and STZ from Santa Cruz Biotechnology (Italy, catalog number sc-200719). AGRP and PG20N, used respectively as MCR1 and MCR5 antagonists, were synthetized as previously described (Carotenuto et al, 2015;Merlino et al, 2018;Merlino et al, 2019).…”

Section: Compoundsmentioning

confidence: 99%

Fingolimod and Diabetic Retinopathy: A Drug Repurposing Study

et al. 2021

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This study aimed to investigate the interactions between fingolimod, a sphingosine 1-phosphate receptor (S1PR) agonist, and melanocortin receptors 1 and 5 (MCR1, MCR5). In particular, we investigated the effects of fingolimod, a drug approved to treat relapsing-remitting multiple sclerosis, on retinal angiogenesis in a mouse model of diabetic retinopathy (DR). We showed, by a molecular modeling approach, that fingolimod can bind with good-predicted affinity to MC1R and MC5R. Thereafter, we investigated the fingolimod actions on retinal MC1Rs/MC5Rs in C57BL/6J mice. Diabetes was induced in C57BL/6J mice through streptozotocin injection. Diabetic and control C57BL/6J mice received fingolimod, by oral route, for 12 weeks and a monthly intravitreally injection of MC1R antagonist (AGRP), MC5R antagonist (PG20N), and the selective S1PR1 antagonist (Ex 26). Diabetic animals treated with fingolimod showed a decrease of retinal vascular endothelial growth factor A (VEGFA) and vascular endothelial growth factor receptors 1 and 2 (VEGFR1 and VEGFR2), compared to diabetic control group. Fingolimod co-treatment with MC1R and MC5R selective antagonists significantly (p < 0.05) increased retinal VEGFR1, VEGFR2, and VEGFA levels compared to mice treated with fingolimod alone. Diabetic animals treated with fingolimod plus Ex 26 (S1PR1 selective blocker) had VEGFR1, VEGFR2, and VEGFA levels between diabetic mice group and the group of diabetic mice treated with fingolimod alone. This vascular protective effect of fingolimod, through activation of MC1R and MC5R, was evidenced also by fluorescein angiography in mice. Finally, molecular dynamic simulations showed a strong similarity between fingolimod and the MC1R agonist BMS-470539. In conclusion, the anti-angiogenic activity exerted by fingolimod in DR seems to be mediated not only through S1P1R, but also by melanocortin receptors.

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“…Generally, a restraining force constant of 1000 kJ/mol nm 2 appears to give the best results. This is a smaller force constant than typical values used in the simulated annealing protocols. ,,− …”

Section: Resultsmentioning

confidence: 92%

Incorporating NOE-Derived Distances in Conformer Generation of Cyclic Peptides with Distance Geometry

Wang

Krummenacher

Landrum

et al. 2022

J. Chem. Inf. Model.

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Nuclear magnetic resonance (NMR) data from NOESY (nuclear Overhauser enhancement spectroscopy) and ROESY (rotating frame Overhauser enhancement spectroscopy) experiments can easily be combined with distance geometry (DG) based conformer generators by modifying the molecular distance bounds matrix. In this work, we extend the modern DG based conformer generator ETKDG, which has been shown to reproduce experimental crystal structures from small molecules to large macrocycles well, to include NOE-derived interproton distances. In noeETKDG, the experimentally derived interproton distances are incorporated into the distance bounds matrix as loose upper (or lower) bounds to generate large conformer sets. Various subselection techniques can subsequently be applied to yield a conformer bundle that best reproduces the NOE data. The approach is benchmarked using a set of 24 (mostly) cyclic peptides for which NOE-derived distances as well as reference solution structures obtained by other software are available. With respect to other packages currently available, the advantages of noeETKDG are its speed and that no prior force-field parametrization is required, which is especially useful for peptides with unnatural amino acids. The resulting conformer bundles can be further processed with the use of structural refinement techniques to improve the modeling of the intramolecular nonbonded interactions. The noeETKDG code is released as a fully open-source software package available at .

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Development of Macrocyclic Peptidomimetics Containing Constrained α,α-Dialkylated Amino Acids with Potent and Selective Activity at Human Melanocortin Receptors

Cited by 14 publications

References 38 publications

Novel temporin L antimicrobial peptides: promoting self-assembling by lipidic tags to tackle superbugs

Novel temporin L antimicrobial peptides: promoting self-assembling by lipidic tags to tackle superbugs

Fingolimod and Diabetic Retinopathy: A Drug Repurposing Study

Incorporating NOE-Derived Distances in Conformer Generation of Cyclic Peptides with Distance Geometry

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