The structure of a designed peptidomimetic inhibitor complex of α-thrombin

Wu, Tswei Ping; Yee, Vivien C.; Tulinksy, A.; Chrusciel, R. A.; Nakanishi, Hiroshi; Shen, Richard; Priebe, Cheryl; Kahn, Michaël

doi:10.1093/protein/6.5.471

Cited by 25 publications

(14 citation statements)

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“…In contrast to the abundance of crystal structures of complexes between thrombin and chemical inhibitors (33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45), our structure is only the second structure of the inhibitor-bound factor Xa. The structure of the DX-9065a-bound factor Xa was the first inhibitor complex structure published (13).…”

Section: Discussionmentioning

confidence: 96%

Structural basis for chemical inhibition of human blood coagulation factor Xa

Kamata

Kawamoto

Honma

et al. 1998

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

133

111

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Factor Xa, the converting enzyme of prothrombin to thrombin, has emerged as an alternative (to thrombin) target for drug discovery for thromboembolic diseases. An inhibitor has been synthesized and the crystal structure of the complex between Des[1-44] factor Xa and the inhibitor has been determined by crystallographic methods in two different crystal forms to 2.3-and 2.4-Å resolution. The racemic mixture of inhibitor FX-2212, (2RS)-(3-amidino-3-biphenylyl)-5-(4-pyridylamino)pentanoic acid, inhibits factor Xa activity by 50% at 272 nM in vitro. The S-isomer of FX-2212 (FX-2212a) was found to bind to the active site of factor Xa in both crystal forms. The biphenylamidine of FX-2212a occupies the S1-pocket, and the pyridine ring makes hydrophobic interactions with the factor Xa aryl-binding site. Several water molecules meditate inhibitor binding to residues in the active site. In contrast to the earlier crystal structures of factor Xa, such as those of apo-Des[1-45] factor Xa and Des[1-44] factor Xa in complex with a naphthyl inhibitor DX-9065a, two epidermal growth factor-like domains of factor Xa are well ordered in both our crystal forms as well as the region between the two domains, which recently was found to be the binding site of the effector cell protease receptor-1. This structure provides a basis for designing next generation inhibitors of factor Xa.Thromboembolic disease is caused by the improper functioning of the blood coagulation process. Blood clots are formed by a zymogen activation cascade of serine proteases, and the last protease of the cascade, thrombin, converts fibrinogen to fibrin, which cross-links to form blood clots (for a review, see ref.

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Section: Discussionmentioning

confidence: 96%

Structural basis for chemical inhibition of human blood coagulation factor Xa

Kamata

Kawamoto

Honma

et al. 1998

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

133

111

View full text Add to dashboard Cite

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“…Examination of x-ray crystal structures of proteolytic enzymes and their endogenous inhibitors (i.e., serpins, Kunitz inhibitors) has demonstrated that an extended strand motif is uniformly adopted by the inhibitor/pseudo-substrate in the enzyme-active site (35,36). A ␤ strand template library enables development of potent specific inhibitors of proteolytic enzymes, such as thrombin, factor VIIa, urokinase-type plasminogen activator, hepatitis C virus protease, and caspase 3 (24,37).…”

Section: Discussionmentioning

confidence: 99%

Tryptase Inhibition Blocks Airway Inflammation in a Mouse Asthma Model

Pae²,

Lee

et al. 2002

The Journal of Immunology

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117

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Release of human lung mast cell tryptase may be important in the pathophysiology of asthma. We examined the effect of the reversible, nonelectrophilic tryptase inhibitor MOL 6131 on airway inflammation and hyper-reactivity in a murine model of asthma. MOL 6131 is a potent selective nonpeptide inhibitor of human lung mast cell tryptase based upon a β-strand template (Ki = 45 nM) that does not inhibit trypsin (Ki = 1,061 nM), thrombin (Ki = 23, 640 nM), or other serine proteases. BALB/c mice after i.p. OVA sensitization (day 0) were challenged intratracheally with OVA on days 8, 15, 18, and 21. MOL 6131, administered days 18–21, blocked the airway inflammatory response to OVA assessed 24 h after the last OVA challenge on day 22; intranasal delivery (10 mg/kg) had a greater anti-inflammatory effect than oral delivery (10 or 25 mg/kg) of MOL 6131. MOL 6131 reduced total cells and eosinophils in bronchoalveolar lavage fluid, airway tissue eosinophilia, goblet cell hyperplasia, mucus secretion, and peribronchial edema and also inhibited the release of IL-4 and IL-13 in bronchoalveolar lavage fluid. However, tryptase inhibition did not alter airway hyper-reactivity to methacholine in vivo. These results support tryptase as a therapeutic target in asthma and indicate that selective tryptase inhibitors can reduce allergic airway inflammation.

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“…One-third of all compounds are proposed to adopt a II or II@ turn type (1,5,7,8,12,16,21,23,31,32,36) and three are designed to mimic a I or I@ turn (13,28,37). All other compounds can either substitute for several kinds of turn or are intended to achieve a chain reversal.…”

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confidence: 99%

“…Eight compounds turned out to be weak or inactive ligands (6,7,9,15,30,33,36,37). The conformations of most of the compounds have been conÐrmed by X-ray structure determination (1, 9È11, 16,19,21,23,28,29,35), NMR spectroscopy (3È6, 12, 13, 17, 20, 22, 26, 27, 30È32, 34, 36) or modelling studies (7,8,14,24,33,37). Surprisingly, to the best of our knowledge, there is only one example (compound 28) where the predicted and the experimentally determined structure of the protein (thrombin) in complex with the ligand was published.28 The importance of peptidomimetics for peptide research is not questioned.…”

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confidence: 99%