DP Technology Nominates Candidate for Lp-PLA2 Inhibitor in DR and DME

DP Technology has recently unveiled DPT0415, a new small molecule aimed at combating diabetic retinopathy (DR) and diabetic macular edema (DME). This compound specifically targets Lipoprotein‐associated phospholipase A2 (Lp-PLA2), a crucial enzyme involved in vascular inflammation and damage to the blood-retinal barrier. The announcement positions DPT0415 as a preclinical candidate, showcasing the capabilities of DP Technology's drug design platform, RiDYMO.

Lp-PLA2 is an enzyme from group VII of the PLA2 superfamily, chiefly released by macrophages. It circulates in the bloodstream bound to low-density lipoprotein (LDL) and high-density lipoprotein (HDL). The enzyme’s activity leads to the formation of lysophosphatidylcholine (lysoPC) from oxidized phospholipids, which then induces vascular inflammation. This inflammation is detrimental to the blood-retinal barrier, marking the pathway towards diabetic retinopathy.

Diabetic retinopathy represents a significant microvascular complication of diabetes and is a leading cause of vision impairment among middle-aged and elderly individuals. Approximately one-third of diabetes patients develop DR. Diabetic macular edema, a condition that can arise at any stage of DR, occurs due to fluid and lipid accumulation in the macula, stemming from the breakdown of the blood-retinal barrier. If the edema reaches the fovea, it results in visual symptoms like metamorphopsia and vision loss.

Current treatments for DME have been revolutionized by the use of intraocular anti-vascular endothelial growth factor (anti-VEGF) drugs. Despite their effectiveness, a substantial number of patients do not experience complete resolution of fluid accumulation, potentially due to the inflammatory nature of DR which involves various cytokines and chemokines. Therefore, it is crucial to explore molecular mechanisms beyond VEGF. As a Lp-PLA2 inhibitor, the oral administration of Darapladib has shown modest improvements in edema and vision in clinical studies, which paves the way for further investigations in this area.

DPT0415 is highlighted as a highly potent, selective, and safe Lp-PLA2 inhibitor, featuring a novel scaffold. At a dose of 0.3 mpk, it demonstrated significant efficacy in rat models of STZ-induced diabetic retinopathy. Preclinical studies have shown that DPT0415 presents higher potency and superior ADME (absorption, distribution, metabolism, and excretion) properties compared to Darapladib, as well as a favorable safety margin.

Xiaomin Zhang, the Head of Drug Discovery at DP Technology, emphasized the potential advantages of DPT0415 over current treatments. As an oral therapy, DPT0415 could mitigate inflammation and vascular leakage, potentially improving vision by targeting Lp-PLA2. This oral administration method may encourage earlier treatment interventions and better outcomes for patients.

Weijie Sun, Founder and CEO of DP Technology, remarked on the company's innovative approach, merging AI, simulation, and experimental methods to address unmet medical needs. Sun highlighted that the discovery of DPT0415 was facilitated by the RiDYMO platform, which employs various modules like Uni-FEP and Uni-QSAR to enhance the compound's potency and ADME properties. Such applications underscore the advancing role of AI in scientific research and drug discovery.

The RiDYMO platform integrates advanced AI and physical algorithms to develop drugs for challenging targets, enhancing the sampling efficiency of molecular dynamics simulations. By leveraging the capabilities of neural networks, RiDYMO can capture dynamic changes in complex biomolecular systems, demonstrating its efficacy in tackling difficult targets like protein-protein interactions and intrinsically disordered proteins.

In conclusion, the nomination of DPT0415 as a preclinical candidate signifies a promising advancement in the treatment of DR and DME, potentially offering a less invasive and more effective therapeutic option. DP Technology's innovative approach and the capabilities of its RiDYMO platform reflect a significant step forward in the field of drug design and development.

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