AAV library screening identifies novel vector for efficient transduction of human aorta.

Targeted gene delivery to vascular smooth muscle cells (VSMCs) could prevent or improve a variety of diseases affecting the vasculature and particularly the aorta. Thus, we aimed to develop a delivery vector that efficiently targets VSMCs. We selected engineered adeno-associated virus (AAV) capsids from a random AAV capsid library and tested the top enriched motifs in parallel screening through individual barcoding.

Extension of the π-system of monoaryl-substituted norbornadienes with acetylene bridges: influence on the photochemical conversion and storage of light energy.

The photochromic norbornadiene/quadricyclane pair is a promising system for molecular solar thermal (MOST) energy storage, with which solar energy may be converted, stored, and released as heat in one integral molecular system. Herein, we present the synthesis of mono-, bis-, and tris-norbornadiene derivatives with alkynylbenzene and alkynylnaphthalene core units, along with studies of their photochemical properties. The target compounds were synthesized by Sonogashira-Hagihara coupling reactions of 2-bromonorbornadiene and the corresponding arylacetylenes.

Targeting PARP-1 and DNA Damage Response Defects in Colorectal Cancer Chemotherapy with Established and Novel PARP Inhibitors.

The DNA repair protein PARP-1 emerged as a valuable target in the treatment of tumor entities with deficiencies of , such as breast cancer. More recently, the application of PARP inhibitors (PARPi) such as olaparib has been expanded to other cancer entities including colorectal cancer (CRC). We previously demonstrated that PARP-1 is overexpressed in human CRC and promotes CRC progression in a mouse model.

Addressing the Intracellular Vestibule of the Plasmodial Lactate Transporter PfFNT by p-Substituted Inhibitors Amplifies In Vitro Activity.

Inhibition of the lactate transporter PfFNT is a valid novel mode of action against malaria parasites. Current pyridine-substituted pentafluoro-3-hydroxy-pent-2-en-1-ones act as substrate analogs with submicromolar EC in vitro, and >99.7% activity in mice.

A Novel 3/4-Fused Indole Scaffold through Acid-Catalyzed Cascade Reaction.

3,4-bridged indoles are underrepresented among the vast number of indoles described in the literature. Attempts to access 3,4-macrocyclized indoles led to the unexpected formation of a novel tetracyclic indole through intramolecular acid-catalyzed ring contraction. The herein-established one-step synthetic route provides an excellent medicinal chemistry platform for the construction of screening libraries covering a unique chemical space of indoles.

Reducing Cardiovascular Disease-An Alternative Approach.

Purpose: Statin drugs are effective at reducing cardiovascular events, but adherence to statin therapy remains a problem for patients and their physicians. We review a paper estimating the economic costs of poor adherence to statin drugs.

Methods: The authors examined two large databases (Medicare and Market Scan databases) including 230,000 patients with hospitalization for myocardial infarction between 2018 and 2019 to determine how many patients were not adhering to guideline-recommended anti-hyperlipidemic medications.

Expanding the Chemical Space of Transforming Growth Factor-β (TGFβ) Receptor Type II Degraders with 3,4-Disubstituted Indole Derivatives.

The TGFβ type II receptor (TβRII) is a central player in TGFβ signaling downstream events, has been linked to cancer progression, and thus, has emerged as an auspicious anti-TGFβ strategy. Especially its targeted degradation presents an excellent goal for effective TGFβ pathway inhibition. Here, cellular structure-activity relationship (SAR) data from the TβRII degrader chemotype was successfully transformed into predictive ligand-based pharmacophore models that allowed scaffold hopping.

Small-Molecule Probes as Pharmacological Tools for the Bone Morphogenetic Protein Signaling Pathway.

The bone morphogenetic protein (BMP) pathway is highly conserved and plays central roles in health and disease. The quality and quantity of its signaling outputs are regulated at multiple levels, offering pharmacological options for targeted modulation. Both target-centric and phenotypic drug discovery (PDD) approaches were applied to identify small-molecule BMP inhibitors and stimulators.

Interpreting the Coronary Artery Calcium Score - Critical Information for the Practicing Physician.

Coronary artery calcium scanning is a routine test for assessing the severity of atherosclerosis in asymptomatic individuals. This inexpensive, noninvasive test quantifies the calcium deposition in the 4 principal coronary arteries. Correct interpretation is important to the physician (for recommending therapy) and to the patient (for determining his or her lifetime risk of a cardiovascular event).

Identification of Maleimide-Fused Carbazoles as Novel Noncanonical Bone Morphogenetic Protein Synergizers.

Morphogenic signaling pathways govern embryonic development and tissue homeostasis on the cellular level. Precise control of such signaling events paves the way for innovative therapeutic approaches in the field of regenerative medicine. In line with these notions, bone morphogenic protein (BMP) is a major osteogenic driver and pharmacological stimulation of BMP signaling holds supreme potential for diseases and defects of the skeleton.

Comparative Effects of Glucose-Lowering Medications on Kidney Outcomes in Type 2 Diabetes: The GRADE Randomized Clinical Trial.

Importance: Type 2 diabetes (T2D) is the leading cause of kidney disease in the US. It is not known whether glucose-lowering medications differentially affect kidney function.

Objective: To evaluate kidney outcomes in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) trial comparing 4 classes of glucose-lowering medications added to metformin for glycemic management in individuals with T2D.

Combined physicochemical and functional assessment of pertuzumab integrity supports extended in-use stability.

Pertuzumab (Perjeta®) is a monoclonal antibody approved for the treatment of HER2-positive breast cancer. Before treatment, the concentrate must be diluted to obtain the ready-to-use infusion solution. Data on the storage stabilities of these preparations are lacking but important for all healthcare professionals in the area of outpatient chemotherapy.

The Highly Potent AhR Agonist Picoberin Modulates Hh-Dependent Osteoblast Differentiation.

Identification and analysis of small molecule bioactivity in target-agnostic cellular assays and monitoring changes in phenotype followed by identification of the biological target are a powerful approach for the identification of novel bioactive chemical matter in particular when the monitored phenotype is disease-related and physiologically relevant. Profiling methods that enable the unbiased analysis of compound-perturbed states can suggest mechanisms of action or even targets for bioactive small molecules and may yield novel insights into biology. Here we report the enantioselective synthesis of natural-product-inspired 8-oxotetrahydroprotoberberines and the identification of Picoberin, a low picomolar inhibitor of Hedgehog (Hh)-induced osteoblast differentiation.

Phenotypic Discovery of Triazolo[1,5-]quinazolines as a First-In-Class Bone Morphogenetic Protein Amplifier Chemotype.

Phenotypic drug discovery (PDD) continues to fuel the research and development pipelines with first-in-class therapeutic modalities, but success rates critically depend on the quality of the underlying model system. Here, we employed a stem cell-based approach for the target-agnostic, yet pathway-centric discovery of small-molecule cytokine signaling activators to act as morphogens during development and regeneration. Unbiased screening identified triazolo[1,5-]quinazolines as a new-in-class in vitro and in vivo active amplifier of the bone morphogenetic protein (BMP) pathway.

Potential for repurposing oral hypertension/diabetes drugs to decrease asthma risk in obesity.

Objective: Risk for asthma in the overweight/obese may be mediated by adiponectin and peroxisome proliferator activated receptor pathways and may be reduced by the use of oral drugs impacting these pathways, such as angiotensin converting enzyme inhibitors (ACE-I), thiazolidinediones (TZD), and angiotensin receptor blockers (ARB). Our study objective was to determine whether ACE-I, TZD, and/or ARB use in overweight/obese adults with diabetes mellitus and/or hypertension is associated with a lower risk for incident asthma.

Methods: Using an existing cohort of American veterans, we performed a longitudinal data analysis over 15 years.

Phenotypic screen identifies FOXO inhibitor to counteract maturation and promote expansion of human iPS cell-derived cardiomyocytes.

Achieving pharmacological control over cardiomyocyte proliferation represents a prime goal in therapeutic cardiovascular research. Here, we identify a novel chemical tool compound for the expansion of human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes. The forkhead box O (FOXO) inhibitor AS1842856 was identified as a significant hit from an unbiased proliferation screen in early, immature hiPSC- cardiomyocytes (eCMs).

Probing Embryonic Development Enables the Discovery of Unique Small-Molecule Bone Morphogenetic Protein Potentiators.

We report on the feasibility to harness embryonic development for the identification of small-molecule cytokine mimetics and signaling activators. Here, a phenotypic, target-agnostic, high-throughput assay is presented that probes bone morphogenetic protein (BMP) signaling during mesodermal patterning of embryonic stem cells. The temporal discrimination of BMP- and transforming growth factor-β (TGFβ)-driven stages of cardiomyogenesis underpins a selective, authentic orchestration of BMP cues that can be recapitulated for the discovery of BMP activator chemotypes.