Small Peptides Blocking Inhibition of Factor Xa and Tissue Factor-Factor VIIa by Tissue Factor Pathway Inhibitor (TFPI)

Dockal, Michael; Hartmann, Rudolf; Fries, Markus; Thomassen, M. Christella L. G. D.; Heinzmann, Alexandra C.A.; Ehrlich, Hartmut J.; Rosing, Jan; Osterkamp, Frank; Polakowski, Thomas; Reineke, Ulrich; Griessner, A.; Brandstetter, Hans; Scheiflinger, Friedrich

doi:10.1074/jbc.m113.533836

Cited by 41 publications

(37 citation statements)

References 43 publications

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“…Such bi-phasic inhibition can be rationalized by conformational rearrangements within the protein–inhibitor complex and are often observed with allosteric inhibition30. To directly assess the inhibition mode, we immobilized compound 11 and the structurally related compound 11b and tested its binding to different human δ-secretase variants by the surface acoustic wave (SAW) method.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of delta-secretase improves cognitive functions in mouse models of Alzheimer’s disease

et al. 2017

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δ-secretase, also known as asparagine endopeptidase (AEP) or legumain, is a lysosomal cysteine protease that cleaves both amyloid precursor protein (APP) and tau, mediating the amyloid-β and tau pathology in Alzheimer's disease (AD). Here we report the therapeutic effect of an orally bioactive and brain permeable δ-secretase inhibitor in mouse models of AD. We performed a high-throughput screen and identified a non-toxic and selective δ-secretase inhibitor, termed compound 11, that specifically blocks δ-secretase but not other related cysteine proteases. Co-crystal structure analysis revealed a dual active site-directed and allosteric inhibition mode of this compound class. Chronic treatment of tau P301S and 5XFAD transgenic mice with this inhibitor reduces tau and APP cleavage, ameliorates synapse loss and augments long-term potentiation, resulting in protection of memory. Therefore, these findings demonstrate that this δ-secretase inhibitor may be an effective clinical therapeutic agent towards AD.

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Section: Resultsmentioning

confidence: 99%

Inhibition of delta-secretase improves cognitive functions in mouse models of Alzheimer’s disease

et al. 2017

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“…19 Other novel experimental agents in development include those that block tissue factor pathway inhibitor, an antifactor IXa/X-bispecific antibody, a zymogen-like factor Xa molecule, and an RNA interference (RNAi) therapeutic targeting antithrombin. [20][21][22][23] Unlike current products that must be given IV, these new products may ultimately lead to adjunctive treatment for patients with hemophilia by subcutaneous or oral routes. Despite the failed development of some agents, the potential of new therapeutics to improve hemostasis in patients with an inhibitor remains promising.…”

Section: Treatment Of Bleedingmentioning

confidence: 99%

Toward optimal therapy for inhibitors in hemophilia

Kempton

Meeks

2014

Blood

134

156

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Treatment of patients with hemophilia A and B has undergone significant advances during the past 2 decades. However, despite these advances, the development of antibodies that inhibit the function of infused clotting factor remains a major challenge and is considered the most significant complication of hemophilia treatment. This chapter reviews current tools available for the care of patients with inhibitors and highlights areas where progress is imminent or strongly needed. For management of bleeding, bypassing agents remain the mainstay of therapy. Recombinant factor VIIa and activated prothrombin complex concentrates are similarly effective in populations of patients with hemophilia and inhibitors; however, individuals may show a better response to one agent over another. Recent studies have shown that prophylaxis with bypassing agents can reduce bleeding episodes by ∼50%-80%. The prophylactic use of bypassing agents is an important tool to reduce morbidity in patients before they undergo immune tolerance induction (ITI) and in those with persistent high titer inhibitors, but cost and lack of convenience remain barriers. Because of the significant burden that inhibitors add to the individual patient and the health care system, inhibitor eradication should be pursued in as many patients as possible. ITI is an effective tool, particularly in patients with severe hemophilia A and good risk profiles, and leads to a return to a normal factor VIII response in ∼60% of patients. However, for the group of patients who fail to respond to ITI or have hemophilia B, new and improved tools are needed.

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“…2,3 Indeed, when the intrinsic tenase pathway leading to factor Xa (FXa) activation is blocked due to FVIII or FIX deficiency, a small amount of FXa can be generated by the extrinsic tenase (FVIIa/tissue factor), but it is immediately neutralized by binding of TFPI through its Kunitz 2 (K2) domain while the Kunitz 1 (K1) domain of TFPI subsequently binds to FVIIa, inhibiting the tenase. 4,5 Our team has postulated an original anti-TFPI strategy, Gla-domainless factor Xa (GD-FXa), deprived of its membrane binding domain, and we have validated the proof of concept of this approach.…”

mentioning

confidence: 99%

Catalytically inactive Gla-domainless factor Xa binds to TFPI and restores ex vivo coagulation in hemophilia plasma

Ersayin¹,

Thomas²,

Seyve³

et al. 2017

Haematologica

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Small Peptides Blocking Inhibition of Factor Xa and Tissue Factor-Factor VIIa by Tissue Factor Pathway Inhibitor (TFPI)

Cited by 41 publications

References 43 publications

Inhibition of delta-secretase improves cognitive functions in mouse models of Alzheimer’s disease

Inhibition of delta-secretase improves cognitive functions in mouse models of Alzheimer’s disease

Toward optimal therapy for inhibitors in hemophilia

Catalytically inactive Gla-domainless factor Xa binds to TFPI and restores ex vivo coagulation in hemophilia plasma

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