Peptide to glycopeptide: glycosylated oligopeptide renin inhibitors with attenuated in vivo clearance properties

Fisher, Jed F.; Harrison, Allen W.; Bundy, Gordon L.; Wilkinson, Karen F.; Rush, Bob D.; Ruwart, Mary J.

doi:10.1021/jm00114a026

Cited by 98 publications

(38 citation statements)

References 4 publications

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“…The attractive features of glycopeptide antibiotics compared to their nonglycosylated counterparts include increased solubility and oral availability (Poujade et al 1983;Fisher et al 1991), increased serum half-life (Powell et al 1993), broader biological activity spectra (Biondi et al 1993;Horvat et al 1993), and stabilization of conformational variants (Laczko et al 1992;Urge et al 1992). The present study was aimed at exploring the functional role of glycosylation in formaecin I by designing various nonglycosylated analogs of the glycopeptide and screening for bioactivity.…”

Section: Resultsmentioning

confidence: 99%

Design of a functionally equivalent nonglycosylated analog of the glycopeptide antibiotic formaecin I

2007

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Various nonglycosylated analogs were designed in order to explore the role of glycosylation in formaecin I, an antibacterial glycopeptide of insect origin. The functional behavior of a designed nonglycosylated analog (P 7 ,endo P 8a ,DT 11 )formaecin I was found to be similar to that of native glycosylated peptide. Both the peptides showed similar antibacterial activities against Escherichia coli and Salmonella strains. The designed nonglycosylated analog (P 7 ,endo P 8a ,DT 11 )formaecin I has low binding affinity to LPS identical to that of native glycopeptide, formaecin I. Both the peptides have similar killing kinetics and are nontoxic to erythrocytes. Formaecin I and designed nonglycosylated (P 7 ,endo P 8a ,DT 11 )formaecin I have no definite conformational features associated with them. The glycosylated residue of threonine in formaecin I and proline residues in designed peptide [(P 7 ,endo P 8a ,DT 11 )formaecin I], possibly help in stabilizing the correct conformation that facilitates presentation of the peptide to its receptor. It is evident that a functionally equivalent nonglycosylated analog of native glycosylated antibacterial peptide can be designed by strategically modifying the sequence.

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Section: Resultsmentioning

confidence: 99%

Design of a functionally equivalent nonglycosylated analog of the glycopeptide antibiotic formaecin I

2007

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“…It has been widely accepted that glycosylation of opioid peptides, which endows them higher hydrophobicity, in contrast also works on the transfer of the compounds passing through the lipophilic BBB. [133][134][135] If incorporated appropriately, the glycosyl moiety will not influence the receptor affinity of the ligand. 136,137 But the syntheses of glycopeptides still has great difficulty, particularly in large scale which has been reviewed recently.…”

Section: B Glycosylationmentioning

confidence: 99%

Endomorphins: potential roles and therapeutic indications in the development of opioid peptide analgesic drugs

Liu

Wang

2011

Medicinal Research Reviews

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The application of endomorphins as clinical available analgesic drugs has been impeded by their relatively poor receptor selectivity compared with alkaloid analgesics, rapid degradation in vivo, inefficient to penetrate the blood-brain barrier (BBB), and undesirable or toxic effects, such as acute tolerance and physical dependence, respiratory depression, and inhibition of gastrointestinal motility. Extensive studies have been performed so far striving to conquer these problems. In this article we review and discuss conformational and topographical modifications of the peptide amide bond and amino acid side groups to attain the most appropriate receptor binding affinity and high receptor selectivity; diverse strategies such as insertion of unnatural amino acids, covalent or noncovalent constraints as well as cyclization of linear peptides to enhance the enzymatic stability; designing of peptidomimetic ligands, glycopeptides, and N-terminal amidinationed analogues (such as incorporating guanidine into endomorphins) to penetrate the BBB. Also, several pertinent examples of bivalent and/or multivalent (such as mixed µ-agonist/δ-antagonist profile) compounds are discussed based on the existing literature and current data intending to give an insight into the development of opioid peptides expressing low tendency to produce acute tolerance and physical dependence.

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“…Accordingly, the introduction of glycan residues can confer a slower clearance of putative peptide therapeutics in vivo. [238] In a recent example, Mehta et al investigated the effect of glycosylation on the enzymatic hydrolysis of peptides. [239] The proteolytic enzyme studied was savinase, a subtilisin-type enzyme.…”

Section: Glycopeptides As Enzyme Substrates or Inhibitorsmentioning

confidence: 99%

Glycopeptide Synthesis and the Effects of Glycosylation on Protein Structure and Activity

Seitz

2000

ChemBioChem

197

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Despite the omnipresence of protein glycosylation in nature, little is known about how the attachment of carbohydrates affects peptide and protein activity. One reason is the lack of a straightforward method to access biologically relevant glycopeptides and glycoproteins. The isolation of homogeneous glycopeptides from natural sources is complicated by the heterogeneity of naturally occuring glycoproteins. It is chemical and chemoenzymatic synthesis that is meeting the challenge to solve this availability problem, thus playing a key role for the advancement of glycobiology. The current art of glycopeptide synthesis, albeit far from being routine, has reached a level of maturity that allows for the access to homogeneous and pure material for biological and medicinal research. Even the ambitious goal of the total synthesis of an entire glycoprotein is within reach. It is demonstrated that with the help of synthetic glycopeptides the effects of glycosylation on protein structure and function can be studied in molecular detail. For example, in immunology, synthetic (tumour-specific) glycopeptides can be used as immunogens to elicit a tumour-cell-specific immune response. Again, synthetic glycopeptides are an invaluable tool to determine the fine specificity of the immune response that can be mediated by both carbohydrate-specific B and T cells. Furthermore, selected examples for the use of synthetic glycopeptides as ligands of carbohydrate-binding proteins and as enzyme substrates or inhibitors are presented.

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Peptide to glycopeptide: glycosylated oligopeptide renin inhibitors with attenuated in vivo clearance properties

Abstract: quinolinylmethybamine, 99071-54-2; methyl 4,7,8,9-tetra-Oacetyl-JV-acetyl-2-chloro-2-deoxy-/3-D-neuraminate, 67670-69-3.

Cited by 98 publications

References 4 publications

Design of a functionally equivalent nonglycosylated analog of the glycopeptide antibiotic formaecin I

Design of a functionally equivalent nonglycosylated analog of the glycopeptide antibiotic formaecin I

Endomorphins: potential roles and therapeutic indications in the development of opioid peptide analgesic drugs

Glycopeptide Synthesis and the Effects of Glycosylation on Protein Structure and Activity

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