Conformational restriction of angiotensin II: cyclic analogs having high potency

Spear, Kerry L.; Brown, Monica S.; Reinhard, Emily J.; McMahon, Ellen G.; Olins, Gillian M.; Palomo, Maria A.; Patton, Dennis R.

doi:10.1021/jm00169a019

Cited by 76 publications

(63 citation statements)

References 12 publications

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“…Contractile response assays showed that all the analogs presented insignificant contractile activity by their interaction with the AT 1 receptor. These results are in opposition to those obtained previously by Spear et al (27) in which some disulfide-bridge-containing analogs showed pressor activity. However, according to Regoli et al (46), the substitution of certain residues in the primary sequence of AII caused a decrease in the pressor activity, as was observed in this work.…”

Section: Discussioncontrasting

confidence: 99%

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Highly Potential Antiplasmodial Restricted Peptides

et al. 2014

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Malaria is an infectious disease responsible for approximately one million deaths annually. The antimalarial effects of angiotensin II and its analogs against Plasmodium gallinaceum and P. falciparum have recently been reported. To evaluate antiplasmodial activity, we synthesized five angiotensin II-restricted analogs containing disulfide bridges. To accomplish this, peptides containing two inserted amino acid residues (cysteine) were synthesized by the Fmoc solid-phase method, purified by liquid chromatography, and characterized by mass spectrometry. Conformational studies were performed by circular dichroism. The results indicated that two of the analogs had higher antiplasmodium activity (92% and 98% activity) than angiotensin II (88% activity), measured by fluorescence microscopy. Results showed that the insertion position must be selected, to preserve the hydrophobic interactions between the non-polar residues, as this affects antiplasmodial activity. The circular dichroism studies suggested that the active analogs as well as the native angiotensin II adopt a β-turn conformation in different solutions. This approach provided insight for understanding the effects of restricting the ring size and position on the bioactivity of angiotensin II and provides a new direction for the design of potential chemotherapeutic agents.

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Section: Discussioncontrasting

confidence: 99%

“…These results are in opposition to those obtained previously by Spear et al . in which some disulfide‐bridge‐containing analogs showed pressor activity. However, according to Regoli et al .…”

Section: Discussionmentioning

confidence: 99%

Highly Potential Antiplasmodial Restricted Peptides

et al. 2014

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“…This cyclisation scheme through the oxidation of the sulfhydryl group has the advantage of limiting the changes in physiochemical properties and bulkiness of the cycle. Note that previous work has shown that cyclisation through these side-chains of AngII led to compounds that can still bind and elicit Gq/11 activation [20,21]. However, the impact on the biased signaling has not been characterized.…”

Section: Introductionmentioning

confidence: 99%

Angiotensin II cyclic analogs as tools to investigate AT1R biased signaling mechanisms

St-Pierre

Cabana

Holleran

et al. 2018

Biochemical Pharmacology

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G protein coupled receptors (GPCRs) produce pleiotropic effects by their capacity to engage numerous signaling pathways once activated. Functional selectivity (also called biased signaling), where specific compounds can bring GPCRs to adopt conformations that enable selective receptor coupling to distinct signaling pathways, continues to be significantly investigated. However, an important but often overlooked aspect of functional selectivity is the capability of ligands such as angiotensin II (AngII) to adopt specific conformations that may preferentially bind to selective GPCRs structures. Understanding both receptor and ligand conformation is of the utmost importance for the design of new drugs targeting GPCRs. In this study, we examined the properties of AngII cyclic analogs to impart biased agonism on the angiotensin type 1 receptor (ATR). Positions 3 and 5 of AngII were substituted for cysteine and homocysteine residues ([SarHcy]AngII, [SarCysHcy]AngII and [SarCys]AngII) and the resulting analogs were evaluated for their capacity to activate the Gq/11, G12, Gi2, Gi3, Gz, ERK and β-arrestin (βarr) signaling pathways via ATR. Interestingly, [SarHcy]AngII exhibited potency and full efficacy on all pathways tested with the exception of the Gq pathway. Molecular dynamic simulations showed that the energy barrier associated with the insertion of residue Phe of AngII within the hydrophobic core of ATR, associated with Gq/11 activation, is increased with [SarHcy]AngII. These results suggest that constraining the movements of molecular determinants within a given ligand by introducing cyclic structures may lead to the generation of novel ligands providing more efficient biased agonism.

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“…The crude deprotected peptides were precipitated with anhydrous diethyl ether, filtered from the ether-soluble products, extracted from the resin with 60% acetonitrile (ACN) in water, and lyophilized. The disulfide bridges were formed by first solubilizing the crude peptides (1 g L À1 ) in an 80% acetic acid solution containing 0.04 mol L À1 iodine [21]. After 40 min the reaction was extracted with water and diethyl ether.…”

Section: Peptide Synthesis Purification and Characterizationmentioning

confidence: 99%

Angiotensin II restricted analogs with biological activity in the erythrocytic cycle of Plasmodium falciparum

Torres

Silva

et al. 2014

J. Pept. Sci.

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The anti-plasmodial activity of conformationally restricted analogs of angiotensin II against Plasmodium gallinaceum has been described. To observe activity against another Plasmodium species, invasion of red blood cells by Plasmodium falciparum was analyzed. Analogs restricted with lactam or disulfide bridges were synthesized to determine their effects and constraints in the peptide-parasite interaction. The analogs were synthesized using tert-butoxycarbonyl and fluoromethoxycarbonyl solid phase methods, purified by liquid chromatography, and characterized by mass spectrometry. Results indicated that the lactam bridge restricted analogs 1 (Glu-Asp-Arg-Orn-Val-Tyr-Ile-His-Pro-Phe) and 3 (Asp-Glu-Arg-Val-Orn-Tyr-Ile-His-Pro-Phe) showed activity toward inhibition of ring formation stage of P. falciparum erythrocytic cycle, preventing invasion in about 40% of the erythrocytes. The disulfide-bridged analog 10 (Cys-Asp-Arg-Cys-Val-Tyr-Ile-His-Pro-Phe) was less effective yet significant, showing a 25% decrease in infection of new erythrocytes. In all cases, the peptides presented no pressor activity, and hydrophobic interactions between the aromatic and alkyl amino acid side chains were preserved, a factor proven important in efficacy against P. gallinaceum. In contrast, hydrophilic interactions between the Asp(1) carboxyl and Arg(2) guanidyl groups proved not to be as important as they were in the case of P. gallinaceum, while interactions between the Arg(2) guanidyl and Tyr(4) hydroxyl groups were not important in either case. The β-turn conformation was predominant in all of the active peptides, proving importance in anti-plasmodial activity. This approach provides insight for understanding the importance of each amino acid residue on the native angiotensin II structure and a new direction for the design of potential chemotherapeutic agents.

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Conformational restriction of angiotensin II: cyclic analogs having high potency

Cited by 76 publications

References 12 publications

Highly Potential Antiplasmodial Restricted Peptides

Highly Potential Antiplasmodial Restricted Peptides

Angiotensin II cyclic analogs as tools to investigate AT1R biased signaling mechanisms

Angiotensin II restricted analogs with biological activity in the erythrocytic cycle of Plasmodium falciparum

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