Virtual screening of the Maybridge library of over 70,000 compounds was performed using a similarity filter, docking and MM-GB/SA post-processing to seek potential non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) and a novel oxadiazole compound was found and several analogs were developed and studied. They showed anti-HIV effects with EC50 values as low as 310 nM.
Methods for increasing the patency of biodegradable, synthetic vascular grafts are provided. The methods include administering one or more cytokines and/or chemokines that promote outward tissue remodeling of the vascular grafts and vascular neotissue formation. The disclosed methods do not require cell seeding of the vascular grafts, thus avoiding many problems associated with cell seeding. Biodegradable, polymeric vascular grafts which provide controlled release of cytokines and/or chemokines at the site of vascular graft implantation are also provided.
OCR 6190 & OCR 4921 have remarkable anti-HIV activity profiles with high potency and anti-viral activity. OCR 6190 is an optimized non-nucleoside reverse transcriptase inhibitors (NNRTI) with 100-fold greater solubility than currently FDA-approved drugs.
OCR 4921 is a proof-of-concept bifunctional chimeric NRTI/NNRTI, as shown below, targeting HIV-1 viral replication.
Frontotemporal dementia (FTD) is known to be caused by loss of function mutations in the secreted protein progranulin but the physiological role of progranulin the brain is not known. Yale investigators found that Progranulin binds the cell surface protein Sortilin as a receptor. Progranulin/sortilin interaction regulates BDNF secretion. Thus, sortilin receptor agonists are predicted to ameliorate deficits in Fronto-Temporal dementia.
Researchers at Yale have identified a specific HPV DNA methylation signature in cervical cells that may have prognostic value for cervical cancer.
Yale researchers have developed biodegradable polymeric microparticles containing one or more active agents for the sustained delivery of ophthalmic drugs. Drugs include latanaprost for glaucoma, and triamcinolone for diabetic retinopathy and uveitis. Drug release has been shown over several months.
Yale investigators have developed a new synthetic platelet to treat hemorrhage. The synthetic platelet resembles the shape of an activated platelet (star burst) and is made from FDA-approved materials, consisting of a nanosphere core and polyethylene glycol (PEG) arms. Our synthetic platelet is capable of forming a barrier to reduce membrane permeability and enhance the sealing on a disrupted blood vessel wall, which is extremely beneficial to promote synthetic platelet aggregation at the site of injury.
Yale researchers have identified Wnt pathway agonists that are commercially available, but previously unassociated with the Wnt pathway activation. In addition, Yale researchers have identified novel members in the class. These compounds synergistically activate Wnt3a/Beta-catenin signaling and enhanced the activity of Wnt in vitro.
Researchers at Yale University have identified a pharmacological mechanism whereby proliferation of oligodendrocytes can be stimulated by activation of ATP-dependent potassium channels (KATP channel) in the plasma membranes of oligodendrocytes. Small molecular weight candidate therapeutic compounds (e.g., Diazoxide) have been identified which activate the KATP channel and which have been shown not only to promote proliferation of oligodendrocyte precursor cells in culture but also to increase myelination in rat brain slices in vitro and to prevent hypomyelination and ventriculomegaly in vivo in newborn mice subjected to chronic sub-lethal hypoxia. One of the KATP channel activators shown to mediate the effect on myelination has also been used therapeutically in infants to treat hyperinsulinemic hypoglycemia.
Yale investigators found that the majority of healthy humans recognized OCR5120 derived immunogenic epitopes and generated CD4 and CD8+ T cell responses. These results demonstrate that the human immune system can respond to OCR5120 and identify the specific immunogenic epitopes derived from this antigen as a matter of surveillance rather than response. Therefore, OCR5120 is an excellent cancer vaccine candidate.