New therapeutic strategies are needed for the growing unmet clinical needs in liver disease and fibrosis. Platelet activation and PDGF activity are recognized as important therapeutic targets; however, no therapeutic approach has yet addressed these two upstream drivers of liver fibrosis. We therefore designed a matrix-targeting glycan therapeutic, SBR-294, to inhibit collagen-mediated platelet activation while also inhibiting PDGF activity. Herein we describe the synthesis and characterization of SBR-294 and demonstrate its potential therapeutic benefits in vitro and in vivo. In vitro SBR-294 was found to bind collagen (EC50 = 23 nM), thereby inhibiting platelet-collagen engagement (IC50 = 60 nM). Additionally, SBR-294 was found to bind all PDGF homodimeric isoforms and to inhibit PDGF-BB mediated hepatic stellate cell activation and proliferation. Translating these mechanisms in vivo, SBR-294 reduced fibrosis by up to 54% in the CCl4 mouse model (p=0.0004), as measured by Sirius red histological analysis. Additional fibrosis measurements were also supportive of the therapeutic benefit in this model. These results support the therapeutic benefit of platelet and PDGF antagonism and warrant further investigation of SBR-294 as a potential treatment for liver fibrosis.

需要新的治疗策略来满足肝病和纤维化方面不断增长的未满足临床需求。血小板活化和 PDGF 活性被认为是重要的治疗靶点；然而，目前还没有治疗方法可以解决肝纤维化的这两个上游驱动因素。因此，我们设计了一种基质靶向聚糖治疗剂 SBR-294，以抑制胶原介导的血小板活化，同时抑制 PDGF 活性。在这里，我们描述了 SBR-294 的合成和表征，并证明了其在体外和体内的潜在治疗益处。体外发现 SBR-294 与胶原蛋白结合 (EC50 = 23 nM)，从而抑制血小板-胶原蛋白的结合 (IC50 = 60 nM)。此外，发现 SBR-294 可结合所有 PDGF 同型二聚体异构体并抑制 PDGF-BB 介导的肝星状细胞活化和增殖。通过在体内转化这些机制，SBR-294 在 CCl4 小鼠模型中减少了高达 54% 的纤维化（p=0.0004），通过天狼星红组织学分析测量。额外的纤维化测量也支持该模型中的治疗益处。这些结果支持血小板和 PDGF 拮抗作用的治疗益处，并值得进一步研究 SBR-294 作为肝纤维化的潜在治疗方法。