Targeting the P-selectin/PSGL-1 pathway: discovery of disease-modifying therapeutics for disorders of thromboinflammation

Escopy, Samira; Chaikof, Elliot L.

doi:10.1016/j.bvth.2024.100015

Cited by 3 publications

(1 citation statement)

References 107 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…P-selectin is a member of the selectin family of cell surface glycoproteins and is rapidly expressed on the surfaces of both platelets and endothelial cells during the course of acute and chronic inflammatory processes. Although P-selectin is an essential mediator of beneficial innate immune responses, the interaction of P-selectin with its cognate ligand, P-selectin glycoprotein-1 (PSGL-1), may also promote adverse maladaptive events underlying a variety of diseases linked to dysregulated inflammatory and thrombotic responses, including venous thromboembolism, cardiovascular disease, stroke, metabolic syndrome, and sickle cell disease, among other disorders. − The significance of P-selectin and PSGL-1 in human diseases linked to thromboinflammation and immunothrombosis has motivated the design of inhibitors that target the P-selectin/PSGL-1 pathway . Nonetheless, while synthetic inhibitors for P-selectin remain an attractive target, the development of high-affinity antagonists continues to pose a significant challenge.…”

Section: Introductionmentioning

confidence: 99%

Insights Derived from the Synthesis of a Complex Core 2 Glycan

Dhakal,

Mandhapati,

Park

et al. 2024

J. Org. Chem.

Self Cite

View full text Add to dashboard Cite

We describe the synthesis of a benzoyl-based C2-O-sLe X -Thr-COOH building block devoid of any aglycone transfer or orthoester-formed byproducts. The absence of byproducts was achieved in the course of both [1 + 1] glycosylation reactions with thiophenol aglycone containing galactose acceptors, as well as a [2 + 2] glycosylation in the presence of a p-methoxy benzyl containing glucosamine-fucose disaccharide. We also report an efficient [2 + 1 + 1] synthesis of a peracetylated sLe X en route to a peracetylated C2-O-sLe X -Thr-COOH. While the total synthesis of the latter compound was recently reported by a related route, the divergent [2 + 1 + 1] synthesis provided good reaction yields for each step of the sequence, establishing this scheme as an alternate approach to the peracetylated C2-O-sLe X -Thr-COOH. Importantly, the current report details the role of a variety of hydroxy-protecting groups, including acetyl, benzoyl, p-methoxy benzyl, and naphthylmethyl that may be considered in designing a route to this complex Core 2 glycan. While we have previously described the use of more glycosylation-friendly naphthylmethyl protecting groups, the current synthesis used p-methoxy benzyl protecting groups with excellent reaction yields, demonstrating the feasibility of applying this side reaction-prone protecting group for this challenging synthesis.

show abstract

Section: Introductionmentioning

confidence: 99%

Insights Derived from the Synthesis of a Complex Core 2 Glycan

Dhakal,

Mandhapati,

Park

et al. 2024

J. Org. Chem.

Self Cite

View full text Add to dashboard Cite

show abstract

Coagulopathy and acute pancreatitis: pathophysiology and clinical treatment

Li,

Tan,

et al. 2024

Front. Immunol.

View full text Add to dashboard Cite

Coagulopathy is a critical pathophysiological mechanism of acute pancreatitis (AP), arising from the complex interplay between innate immune, endothelial cells and platelets. Although initially beneficial for the host, uncontrolled and systemic activation of coagulation cascade in AP can lead to thrombotic and hemorrhagic complications, ranging from subclinical abnormalities in coagulation tests to severe clinical manifestations, such as disseminated intravascular coagulation. Initiation of coagulation activation and consequent thrombin generation is caused by expression of tissue factor on activated monocytes and is ineffectually offset by tissue factor pathway inhibitor. At the same time, endothelial-associated anticoagulant pathways, in particular the protein C system, is impaired by pro-inflammatory cytokines. Also, fibrin removal is severely obstructed by inactivation of the endogenous fibrinolytic system, mainly as a result of upregulation of its principal inhibitor, plasminogen activator inhibitor type 1. Finally, increased fibrin generation and impaired break down lead to deposition of (micro) vascular clots, which may contribute to tissue ischemia and ensuing organ dysfunction. Despite the high burden of coagulopathy that have a negative impact on AP patients’ prognosis, there is no effective treatment yet. Although a variety of anticoagulants drugs have been evaluated in clinical trials, their beneficial effects are inconsistent, and they are also characterized by hemorrhagic complications. Future studies are called to unravel the pathophysiologic mechanisms involved in coagulopathy in AP, and to test novel therapeutics block coagulopathy in AP.

show abstract

Targeted Delivery to Dying Cells Through P-Selectin–PSGL-1 Axis: A Promising Strategy for Enhanced Drug Efficacy in Liver Injury Models

Lien,

Sun,

Chang

2024

Cells

View full text Add to dashboard Cite

To minimize off-target adverse effects and improve drug efficacy, various tissue-specific drug delivery systems have been developed. However, even in diseased organs, both normal and stressed, dying cells coexist, and a targeted delivery system specifically for dying cells has yet to be explored to mitigate off-target effects within the same organ. This study aimed to establish such a system. By examining the surfaces of dying cells in vitro, we identified P-selectin glycoprotein ligand-1 (PSGL-1) as a universal marker for dying cells, positioning it as a potential target for selective drug delivery. We demonstrated that liposomes conjugated with the PSGL-1 binding protein P-selectin had significantly greater binding efficiency to dying cells compared to control proteins such as E-selectin, L-selectin, galectin-1, and C-type lectin-like receptor 2. Using thioacetamide (TAA) to induce hepatitis and hepatocyte damage in mice, we assessed the effectiveness of our P-selectin-based delivery system. In vivo, P-selectin-conjugated liposomes effectively delivered fluorescent dye and the apoptosis inhibitor z-DEVD to TAA-damaged livers in wild-type mice, but not in PSGL-1 knockout mice. In TAA-treated wild-type mice, unconjugated liposomes required a 100-fold higher z-DEVD dose compared to P-selectin-conjugated liposomes to achieve a comparable, albeit less effective, therapeutic outcome in lowering plasma alanine transaminase levels and alleviating thrombocytopenia. This emphasizes that P-selectin conjugation enhances drug delivery efficiency by approximately 100-fold in mice. These results suggest that P-selectin-based liposomes could be a promising strategy for targeted drug delivery, enabling both diagnosis and treatment by specifically delivering cell-labeling agents and rescue agents to dying cells via the P-selectin–PSGL-1 axis at the individual cell level.

show abstract

Targeting the P-selectin/PSGL-1 pathway: discovery of disease-modifying therapeutics for disorders of thromboinflammation

Cited by 3 publications

References 107 publications

Insights Derived from the Synthesis of a Complex Core 2 Glycan

Insights Derived from the Synthesis of a Complex Core 2 Glycan

Coagulopathy and acute pancreatitis: pathophysiology and clinical treatment

Targeted Delivery to Dying Cells Through P-Selectin–PSGL-1 Axis: A Promising Strategy for Enhanced Drug Efficacy in Liver Injury Models

Contact Info

Product

Resources

About