Synthesis, biological activity, and fluorine-19 nuclear magnetic resonance spectra of angiotensin II analogs containing fluorine

Vine, William; Brueckner, David A.; Needleman, Philip; Marshall, Garland R.

doi:10.1021/bi00732a026

Cited by 34 publications

(8 citation statements)

References 40 publications

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“…In limited studies, myriad effects of fluorination on hormonal and antimicrobial peptides − have been documented. For example, replacement of Tyr4 and Phe8 with 4F-Phe resulted in two angiotensin II analogues with distinct functional profiles.…”

Section: Introductionmentioning

confidence: 99%

Influence of Selective Fluorination on the Biological Activity and Proteolytic Stability of Glucagon-like Peptide-1

Krishnaji

Beinborn

et al. 2008

J. Med. Chem.

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The relative simplicity and high specificity of peptide therapeutics has fueled recent interest. However, peptide and protein drugs generally require injection and suffer from low metabolic stability. We report here the design, synthesis and characterization of fluorinated analogues of the gut hormone peptide, GLP-1. Overall, fluorinated GLP-1 analogues displayed higher proteolytic stability with simultaneous retention of biological activity (efficacy). Fluorinated amino acids are useful for engineering peptide drug candidates and probing ligand-receptor interactions.

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Section: Introductionmentioning

confidence: 99%

Influence of Selective Fluorination on the Biological Activity and Proteolytic Stability of Glucagon-like Peptide-1

Krishnaji

Beinborn

et al. 2008

J. Med. Chem.

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“…The evidence for this conclusion was that the carbon-13 NMR spectrum at and above neutral pH of the COOH-terminal hexapeptide fragment of [Val5]angiotensin II showed a resonance of the required intensity at the position expected for proline C-'y when proline is in the cis configuration. The pH dependence of the conformation of angiotensin observed by NMR is well documented (4,5,(12)(13)(14) and the possible relationship of this conformational change with pK -6.5 to myotropic activity has been discussed (5, 13). We show here by '3C NMR that both [Asp1,Tyr8]angiotensin II isomerize from alltrans at acidic p2H to partly cis at alkaline p2H and that this isomerization is reported by the His6 C-2 (and C-4) protons.…”

mentioning

confidence: 98%

Correlation of the biological activity and solution conformation of [Asp1,Ile5]- and [Phe4,Tyr8]angiotensin II.

Bleich¹,

Freer²,

Stafford³

et al. 1978

Proc. Natl. Acad. Sci. U.S.A.

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Angiotensin I is known to undergo a reversible conformational transition and a change in potency in rat uterus in vitro with pK -6.5. We have shown by carbon-13 NMR that the conformational transition involves all-trans to partly cis isomerization of the His6-Pro7 peptide bond. Isomerization from all-trans at pH 6.8 to "16% cis at pH 8.0 is therefore correlated with a 10-fold increase in biological activity for [Asp',IJeWJ angiotensin II in rat uterus in vitro. Isomerization from all-trans at pH 6.8 to "16% cis at pH 8.0 in the competitive inhibitor [Phe4,Tyr8Jangiotensin II is correlated with exhibition of virtually no agonist activity at low pH to full agonist activity at high pH. An angiotensin II conformation with Pro7 in the cis form may therefore be the conformation with maximal binding or biological activity at the cellular receptor.Our understanding of the physical and chemical basis for the biological activity of angiotensin II has progressed along two largely independent pathways. The investigation of the biological activity of a large number of analogs (summarized in refs. 1-3) has clarified the role that various residues or groups of residues play in that activity. The investigation of the solution conformation of angiotensin II and of various analogs has made use of most biophysical methods available (summarized in refs. 4 and 5), and several models for the solution conformation have been proposed (5-9). Although most investigators agree that a compact and more or less rigid conformation does exist, no agreement on a definite model has been reached. We suggest that the biological potency of "native" angiotensin II § and of [Phe4,Tyr8]angiotensin II as a function of pH may be related to the amount of cis configuration of Pro7 present in solution. The [Phe4,Tyr8] analog of angiotensin II has been observed to be an antagonist at low pH and an agonist above pH 7 (11).The present study is based on our earlier observations (10) that at low pH in aqueous solution angiotensin II is present in a conformation having proline in the trans configuration and above pH 6.5 two conformations are observed by nuclear magnetic resonance (NMR), an abundant conformation (88%) with proline in the trans configuration and a minor conformation (12%) with proline in the cis configuration. The evidence for this conclusion was that the carbon-13 NMR spectrum at and above neutral pH of the COOH-terminal hexapeptide fragment of [Val5]angiotensin II showed a resonance of the required intensity at the position expected for proline C-'y when proline is in the cis configuration. The pH dependence of the conformation of angiotensin observed by NMR is well documented (4,5,(12)(13)(14) and the possible relationship of this conformational change with pK -6.5 to myotropic activity has been discussed (5, 13). We show here by '3C NMR that both [Asp1,Tyr8]angiotensin II isomerize from alltrans at acidic p2H to partly cis at alkaline p2H and that this isomerization is reported by the His6 C-2 (and C-4) protons. Other conformational...

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“…The trifluoroacetyl moiety has been chemically bound to ribonuclease and hemoglobin and studied using 19Fnmr techniques Raftery, 1971, 1972a-c). 19F-Nmr has also been used to study the conformation of angiotensin II analogs (Vine et al, 1973).…”

mentioning

confidence: 99%

Fluorine nuclear magnetic resonance studies of trifluoroacetyl-insulin derivatives. Effect of pH on conformation and aggregation

Paselk¹,

Lévy²

1974

Biochemistry

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Synthesis, biological activity, and fluorine-19 nuclear magnetic resonance spectra of angiotensin II analogs containing fluorine

Cited by 34 publications

References 40 publications

Influence of Selective Fluorination on the Biological Activity and Proteolytic Stability of Glucagon-like Peptide-1

Influence of Selective Fluorination on the Biological Activity and Proteolytic Stability of Glucagon-like Peptide-1

Correlation of the biological activity and solution conformation of [Asp1,Ile5]- and [Phe4,Tyr8]angiotensin II.

Fluorine nuclear magnetic resonance studies of trifluoroacetyl-insulin derivatives. Effect of pH on conformation and aggregation

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