Current Topics in Medicinal Chemistry - Volume 19, Issue 20, 2019

Proteolysis targeting chimeras (PROTACs), as a novel therapeutic modality, play a vital role in drug discovery. Each PROTAC contains three key parts; a protein-of-interest (POI) ligand, a E3 ligase ligand, and a linker. These bifunctional molecules could mediate the degradation of POIs by hijacking the activity of E3 ubiquitin ligases for POI ubiquitination and subsequent degradation via the ubiquitin proteasome system (UPS). With several advantages over other therapeutic strategies, PROTACs have set off a new upsurge of drug discovery in recent years. ENDTAC, as the development of PROTACs technology, is now receiving more attention. In this review, we aim to summarize the rapid progress from 2018 to 2019 in protein degradation and analyze the challenges and future direction that need to be addressed in order to efficiently develop potent protein degradation technology.

Background: Cardiovascular diseases remain the leading cause of morbidity and mortality in the world, with elevated Low-Density Lipoprotein-Cholesterol (LDL-C) levels as the major risk factor. Lower levels of LDL-C can effectively reduce the risk of cardiovascular diseases. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in regulating the degradation of hepatic LDL receptors that remove LDL-C from the circulation. PCSK9 inhibitors are a new class of agents that are becoming increasingly important in the treatment to reduce LDL-C levels. Two PCSK9 inhibitors, alirocumab and evolocumab, have been approved to treat hypercholesterolemia and are available in the United States and the European Union. Through the inhibition of PCSK9 and increased recycling of LDL receptors, serum LDL-C levels can be significantly reduced. Objective: This review will describe the chemistry, pharmacokinetics, and pharmacodynamics of PCSK9 inhibitors and their clinical effects.

Type 2 diabetes mellitus is one of the most common forms of the disease worldwide. Hyperglycemia and insulin resistance play key roles in type 2 diabetes mellitus. Renal glucose reabsorption is an essential feature in glycaemic control. Kidneys filter 160 g of glucose daily in healthy subjects under euglycaemic conditions. The expanding epidemic of diabetes leads to a prevalence of diabetes-related cardiovascular disorders, in particular, heart failure and renal dysfunction. Cellular glucose uptake is a fundamental process for homeostasis, growth, and metabolism. In humans, three families of glucose transporters have been identified, including the glucose facilitators GLUTs, the sodium-glucose cotransporter SGLTs, and the recently identified SWEETs. Structures of the major isoforms of all three families were studied. Sodium-glucose cotransporter (SGLT2) provides most of the capacity for renal glucose reabsorption in the early proximal tubule. A number of cardiovascular outcome trials in patients with type 2 diabetes have been studied with SGLT2 inhibitors reducing cardiovascular morbidity and mortality. The current review article summarises these aspects and discusses possible mechanisms with SGLT2 inhibitors in protecting heart failure and renal dysfunction in diabetic patients. Through glucosuria, SGLT2 inhibitors reduce body weight and body fat, and shift substrate utilisation from carbohydrates to lipids and, possibly, ketone bodies. These pleiotropic effects of SGLT2 inhibitors are likely to have contributed to the results of the EMPA-REG OUTCOME trial in which the SGLT2 inhibitor, empagliflozin, slowed down the progression of chronic kidney disease and reduced major adverse cardiovascular events in high-risk individuals with type 2 diabetes. This review discusses the role of SGLT2 in the physiology and pathophysiology of renal glucose reabsorption and outlines the unexpected logic of inhibiting SGLT2 in the diabetic kidney.

Notwithstanding substantial improvements in diagnosis and treatment, Heart Failure (HF) remains a major disease burden with high prevalence and poor outcomes worldwide. Natriuretic Peptides (NPs) modulate whole cardiovascular system and exhibit multiple cardio-protective effects, including the counteraction of the Renin–Angiotensin–Aldosterone System (RAAS) and Sympathetic Nervous System (SNS), promotion of vasodilatation and natriuresis, and inhibition of hypertrophy and fibrosis. Novel pharmacological therapies based on NPs may achieve a valuable shift in managing patients with HF from inhibiting RAAS and SNS to a reversal of neurohormonal imbalance. Enhancing NP bioavailability through exogenous NP administration and inhibiting Neutral Endopeptidase (NEP) denotes valuable therapeutic strategies for HF. On the one hand, NEP-resistant NPs may be more specific as therapeutic choices in patients with HF. On the other hand, NEP Inhibitors (NEPIs) combined with RAAS inhibitors have proved to exert beneficial effects and reduce adverse events in patients with HF. Highly effective and potentially safe Angiotensin Receptor Blocker Neprilysin Inhibitors (ARNIs) have been developed after the failure of NEPIs and Vasopeptidase Inhibitors (VPIs) due to lacking efficacy and safety. Therapeutic progress and knowledge basis on the NP system in HF are summarized in the current review.