Biology subjects

Xiong, J.-P.

Publications and source records attributed to Xiong, J.-P..

3 recordsLinked to original sources

bioRxiv2024

Platelet integrin αIIbβ3 plays a key role in venous thrombogenesis in a mouse model

AbstractVenous thrombosis (VT) is a common vascular disease associated with reduced survival and a high recurrence rate. Previous studies have shown that the accumulation of platelets and neutrophils at sites of endothelial cell activation is a primary event in VT, but a role for platelet IIb{beta}3 in the initiation of venous thrombosis has not been established. This task has been complicated by the increased bleeding linked to partial agonism of current IIb{beta}3 inhibitory drugs such as tirofiban (Aggrastat(R)). Here, we show that m-tirofiban, an engineered version of tirofiban, is not a partial agonist of IIb{beta}3. This is based on its cryo-EM structure in complex with human full-length IIb{beta}3 and its inability to increase expression of an activation-sensitive epitope on platelet IIb{beta}3. m-tirofiban abolished agonist-induced platelet aggregation ex vivo at concentrations that preserved clot retraction and markedly suppressed the accumulation of platelets, neutrophils, and fibrin on thrombin-activated endothelium in real-time using intravital microscopy in a mouse model of venous thrombogenesis. Unlike tirofiban, however, m-tirofiban did not increase bleeding at the thrombosis-inhibitory dose. These findings establish a key role for IIb{beta}3 in the initiation of VT, provide a guiding principle for designing potentially safer inhibitors for other integrins, and suggest that pure antagonists of IIb{beta}3 like m-tirofiban merit further consideration as potential thromboprophylaxis agents in patients at high-risk for VT and hemorrhage.

pathology↗

bioRxiv2019

Structural basis of the differential binding of engineered knottins 2.5F and 2.5D to integrins αVβ3 and α5β1

Integrins V{beta}3 and 5{beta}1 play critical roles in tumor survival, invasion, metastasis, and angiogenesis and are validated targets for cancer therapy and molecular imaging. Increasing evidence suggests that targeting both integrins simultaneously with antagonists is more effective in cancer therapy because of concerns about resistance and paradoxical promotion of tumor growth with use of agents highly selective for a single integrin. Engineered Arg-Gly-Asp (RGD)-containing 3.5 kDa cysteine-knot proteins (knottins 2.5F and 2.5D) are attractive drug candidates due to their exceptional structural stability and high affinity binding to certain integrins. 2.5F binds both V{beta}3 and 5{beta}1, whereas 2.5D is V{beta}3-selective. To elucidate the structural basis of integrin selection, we determined the structures of 2.5F and 2.5D both as apo-proteins and in complex with V{beta}3. These data, combined with MD simulations and mutational studies, revealed a critical role of two V{beta}3-specific residues in the vicinity of the metal ion dependent adhesion site (MIDAS) in promoting an V{beta}3-induced fit of 2.5D. In contrast, conformational selection accounted for the specificity of 2.5F to both integrins. These data provide new insights into the structural basis of integrin-ligand binding specificity, and could help in development of integrin-targeted therapeutics.

molecular biology↗

bioRxiv2018

Structure-guided design of a pure orthosteric antagonist of integrin αIIbβ3 that inhibits thrombosis but not clot retraction

Platelet integrin lIb{beta}3 plays a critical role in both hemostasis and thrombosis. Current IIb{beta}3 antagonists are potent anti-thrombotic drugs, but also cause adverse outcomes, which limited their clinical use. Drug-induced serious bleeding, thrombocytopenia and paradoxical thrombosis have been linked to impaired clot retraction and to conformational changes in IIb{beta}3 that promote binding of preformed antibodies, natural ligands or both to IIb{beta}3. We have used structure-guided design to generate the orthosteric inhibitor Hr10 that acts as a pure IIb{beta}3 antagonist, i.e. it does not induce the conformational changes in IIb{beta}3. Hr10 is as effective as the partial agonist drug eptifibatide in blocking platelet aggregation and arteriolar thrombosis in mice. In contrast to eptifibatide, however, Hr10 preserved thrombin-induced clot retraction, suggesting that it may not perturb hemostasis. Our structure-based approach can find general utility in designing pure orthosteric inhibitors for other integrins, in providing vital tools for dissecting structure-activity relationships in IIb{beta}3, and potentially in offering safer alternatives for human therapy.

cell biology↗