Aromatic interactions with naphthylalanine in a <i>β</i>‐hairpin peptide

Meyer, Daniel; Mutschler, Caleb; Robertson, Ian M.; Batt, Alexandra; Tatko, Chad D.

doi:10.1002/psc.2496

Cited by 9 publications

(6 citation statements)

References 57 publications

(55 reference statements)

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“…The NMR-based structural model of TCMCB07 (Figure ) suggests a hydrogen bond (see arrow) between Asp 2 (CO) and Arg 5 (N–H) that contributes to ring stabilization. The NMR results are consistent with the evidence that pairing of aromatic and proline residues contributes to peptide stabilization into a hairpin. , …”

Section: Resultssupporting

confidence: 86%

“…The NMR results are consistent with the evidence that pairing of aromatic and proline residues contributes to peptide stabilization into a hairpin. 105 Though NOEs support a β turn in TCMCB03, 15 N NMR (T 2 ) relaxation studies suggest the backbone of TCMCB03 is more flexible than that of TCMCB07 (see Supporting Information, Table S5). Thus, the His 3 substitution for Pro 3 in TCMCB03 appears to destabilize the TCMCB07 hairpin secondary structure.…”

Section: Resultsmentioning

confidence: 99%

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Development of a Therapeutic Peptide for Cachexia Suggests a Platform Approach for Drug-like Peptides

Gruber

Gallazzi

et al. 2022

ACS Pharmacol. Transl. Sci.

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During the development of a melanocortin (MC) peptide drug to treat the condition of cachexia (a hypermetabolic state producing lean body mass wasting), we were confronted with the need for peptide transport across the blood–brain barrier (BBB): the MC-4 receptors (MC4Rs) for metabolic rate control are located in the hypothalamus, i.e., behind the BBB. Using the term “peptides with BBB transport”, we screened the medical literature like a peptide library. This revealed numerous “hits”peptides with BBB transport and/or oral activity. We noted several features common to most peptides in this class, including a dipeptide sequence of nonpolar residues, primary structure cyclization (whole or partial), and a Pro-aromatic motif usually within the cyclized region. Based on this, we designed an MC4R antagonist peptide, TCMCB07, that successfully treated many forms of cachexia. As part of our pharmacokinetic characterization of TCMCB07, we discovered that hepatobiliary extraction from blood accounted for a majority of the circulating peptide’s excretion. Further screening of the literature revealed that TCMCB07 is a member of a long-forgotten peptide class, showing active transport by a multi-specific bile salt carrier. Bile salt transport peptides have predictable pharmacokinetics, including BBB transport, but rapid hepatic clearance inhibited their development as drugs. TCMCB07 shares the general characteristics of the bile salt peptide class but with a much longer half-life of hours, not minutes. A change in its C-terminal amino acid sequence slows hepatic clearance. This modification is transferable to other peptides in this class, suggesting a platform approach for producing drug-like peptides.

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Section: Resultssupporting

confidence: 86%

Section: Resultsmentioning

confidence: 99%

Development of a Therapeutic Peptide for Cachexia Suggests a Platform Approach for Drug-like Peptides

Gruber

Gallazzi

et al. 2022

ACS Pharmacol. Transl. Sci.

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“…2 ). Meyer et al studied the substitution of aromatic residues as Pro and Trp by 2-Nal and 1-Nal residues in a β-hairpin peptide [ 39 ]. They observed that the molecular geometry was maintained intact when Phe was replaced by 2-Nal residue [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

New linear antiplasmodial peptides related to angiotensin II

Silva

Torres

Silva

et al. 2015

Malar J

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BackgroundAntiplasmodial activities of angiotensin II and its analogues have been extensively investigated in Plasmodium gallinaceum and Plasmodium falciparum parasite species. Due to its vasoconstrictor property angiotensin II cannot be used as an anti-malarial drug.MethodsThis work presents the solid-phase syntheses and liquid chromatography and mass spectrometry characterization of ten linear peptides related to angiotensin II against mature P. gallinaceum sporozoites and erythrocyte invasion by P. falciparum. Conformational analyses were performed by circular dichroism. IC50 assays were performed to identify the ideal concentration used on the biological tests and haemolytical erythrocytic assays were made to verify the viability of the biological experiments. The contractile responses of the analogues were made to evaluate if they are promising candidates to be applied as antiplasmodial drugs.ResultsThe results indicate two short-peptides constituted by hydrophobic residues (5 and 6) with antiplasmodial activity in these models, 89 and 94 % of biological activity against P. gallinaceum sporozoite, respectively, and around 50 % of activity against P. falciparum. Circular dichroism spectra suggested that all the peptides adopted β-turn conformation in different solutions, except peptide 3. Besides the biological assays IC50, the haemolysis assays and contractile response activities were applied for peptides 5 and 6, which did not present expressive results.ConclusionsThe hydrophobic portion and the arginine, tyrosine, proline, and phenylalanine, when present on peptide primary sequence, tend to increase the antiplasmodial activity. This class of peptides can be explored, as anti-malarial drugs, after in vivo model tests.Graphical abstract:The most active peptide presented 94 % activity on P. gallinaceum sporozoites and 53 % inhibited P. falciparum ring forms invasionElectronic supplementary materialThe online version of this article (doi:10.1186/s12936-015-0974-y) contains supplementary material, which is available to authorized users.

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“…Naphthyl-alanine (Nal) is often used to mimic tryptophan (Trp) and to explore potential improvements in peptide pharmacological profiles [40][41][42]; however, it is not clear if 1-Nal or 2-Nal adequately replicate the effects of Trp aromatic interactions. In fact, as with any modification, the consequence of these replacements upon the peptide potency needs careful assessment, because it has been demonstrated that substitution of Trp with 1-Nal or 2-Nal decreases the potency of cholecystokinin analogues [43].…”

Section: Non-natural Amino Acids Occurrencementioning

confidence: 99%