Structure‐Based Design of Residue 1 Analogs of the Direct Thrombin Inhibitor Pentapeptide FM 19

Girnys, Elizabeth A.; Sobczyk-Kojiro, Katarzyna; Mosberg, Henry I.

doi:10.1111/j.1747-0285.2009.00915.x

Cited by 5 publications

(2 citation statements)

References 16 publications

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“…More recent approaches include the study of several synthetic analogs of the angiotensin converting enzyme breakdown product of bradykinin (RPPGF) [17], [18], [19], [20] as well as 1,3,5-trisubstituted benzenes [21] as potent thrombin inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Rational Design and Characterization of D-Phe-Pro-D-Arg-Derived Direct Thrombin Inhibitors

et al. 2012

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The tremendous social and economic impact of thrombotic disorders, together with the considerable risks associated to the currently available therapies, prompt for the development of more efficient and safer anticoagulants. Novel peptide-based thrombin inhibitors were identified using in silico structure-based design and further validated in vitro. The best candidate compounds contained both l- and d-amino acids, with the general sequence d-Phe(P3)-Pro(P2)-d-Arg(P1)-P1′-CONH2. The P1′ position was scanned with l- and d-isomers of natural or unnatural amino acids, covering the major chemical classes. The most potent non-covalent and proteolysis-resistant inhibitors contain small hydrophobic or polar amino acids (Gly, Ala, Ser, Cys, Thr) at the P1′ position. The lead tetrapeptide, d-Phe-Pro-d-Arg-d-Thr-CONH2, competitively inhibits α-thrombin's cleavage of the S2238 chromogenic substrate with a Ki of 0.92 µM. In order to understand the molecular details of their inhibitory action, the three-dimensional structure of three peptides (with P1′ l-isoleucine (fPrI), l-cysteine (fPrC) or d-threonine (fPrt)) in complex with human α-thrombin were determined by X-ray crystallography. All the inhibitors bind in a substrate-like orientation to the active site of the enzyme. The contacts established between the d-Arg residue in position P1 and thrombin are similar to those observed for the l-isomer in other substrates and inhibitors. However, fPrC and fPrt disrupt the active site His57-Ser195 hydrogen bond, while the combination of a P1 d-Arg and a bulkier P1′ residue in fPrI induce an unfavorable geometry for the nucleophilic attack of the scissile bond by the catalytic serine. The experimental models explain the observed relative potency of the inhibitors, as well as their stability to proteolysis. Moreover, the newly identified direct thrombin inhibitors provide a novel pharmacophore platform for developing antithrombotic agents by exploring the conformational constrains imposed by the d-stereochemistry of the residues at positions P1 and P1′.

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Section: Introductionmentioning

confidence: 99%

Rational Design and Characterization of D-Phe-Pro-D-Arg-Derived Direct Thrombin Inhibitors

et al. 2012

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“…In fact, the biological information of a protein sequence appears to reside in short aa strings. (31) A minimotif of only five residues can determine or inhibit essential cellular functions and processes such as cell adhesion and nerve regeneration, (32,33) apoptosis, (34) cancer cell proliferation (35) or migration, (36) thrombin activity, (37) and angiogenesis. (38) Moreover, it is well known that a pentapeptide represents a minimal recognition unit at the basis of the immune response, (39,40) and has an immunotherapeutic potential.…”

Section: Resultsmentioning

confidence: 99%

A peptide talk between JC virus and the human host: from silent infection to autoimmunity

Lucchese¹

2012

Immunopharmacology and Immunotoxicology

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Analysis of JC virus (JCV) polyprotein for peptide sharing with the human proteome reveals that the virus has hundreds of pentapeptide sequences in common with the human proteins. The datum is interesting in light of the fundamental role exerted by short amino acid sequences in protein-protein interactions and, consequently, in biochemical reactions and immune recognition. Searching for new approaches to understand the JCV infection scenarios, from the immunoevasion phenomenon underlying the viral asymptomatic stay in the human host to the (re)activation phase and associated pathogenic sequelae, the present study describes the diffuse pentapeptide communication network between JCV and the human host.

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Access to the cis‐Fused Stereoisomers of Proline Analogues Containing an Octahydroindole Core

et al. 2011

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An overview of the synthetic methods developed to build all the cis‐fused stereoisomers of octahydroindole‐2‐carboxylic acid and its α‐methylated derivative in enantiomerically pure form is presented. Both asymmetric synthetic strategies(auxiliary‐ or substrate‐controlled processes) and procedures based on the resolution of racemic compounds (chemical, enzymatic, and chromatographic processes) are summarized. Special emphasis has been placed on those strategies able to provide multigram quantities of enantiopure compounds, a prerequisite to make downstream biological applications feasible.

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Structure‐Based Design of Residue 1 Analogs of the Direct Thrombin Inhibitor Pentapeptide FM 19

Cited by 5 publications

References 16 publications

Rational Design and Characterization of D-Phe-Pro-D-Arg-Derived Direct Thrombin Inhibitors

Rational Design and Characterization of D-Phe-Pro-D-Arg-Derived Direct Thrombin Inhibitors

A peptide talk between JC virus and the human host: from silent infection to autoimmunity

Access to the cis‐Fused Stereoisomers of Proline Analogues Containing an Octahydroindole Core

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