Current Medicinal Chemistry - Volume 24, Issue 31, 2017

Background: Family B G protein-coupled receptors (GPCRs) play an important role in many physiological and pathophysiological processes. They are plasma-membrane proteins containing an extracellular N-domain, an intracellular C-tail, seven transmembrane domains (TMs), three extracellular (ELs) and three intracellular (ILs) loops. Objective: This review aims to summarize the current structural and functional information for family B GPCRs and their ligands, as well as, their physiological and pathophysiological role. Methods: thorough search of bibliographic databases for peer-reviewed research literature was undertaken. Moreover, molecular models of family B GPCRs were constructed and a structural alignment of their amino acid sequences was performed to demonstrate common structural characteristics. Results: In this review the family B GPCRs and their complexes with the receptor activity modifying proteins (RAMPs) were classified into five groups and the important physiological and pathophysiological role of these receptors was summarized. In addition, conserved residues of the Ndomain and the TMs of these receptors were numbered, thus making feasible the comparison of receptor structures and demonstrating common structural characteristics that are functionally important for all family B receptors. Molecular models created in this study were used to discuss the molecular mechanisms underlying ligand binding to family B GPCRs and receptor activation. Conclusion: The findings of this review provide information about the structural-functional determinants of family B GPCRs and their ligands, thus boosting the design of novel drugs with better potencies and bioavailabilities, which might enrich the therapeutic armory for the treatment of a wide spectrum of family B GPCRs-related disorders.

Background: Research on Chromogranin A (CGA) and its derived fragments convincingly demonstrated the multifunctional activity of the 21 amino acid peptide named Catestatin (CST: human CGA352-372, bovine CGA344-364, rat CGA367-387). This review aims to provide a synopsis of the current information concerning the biological role of CST in health and disease. Methods: Structured search of bibliographic databases for peer-reviewed research literature. Results: CST is mainly known as an inhibitor of the nicotinic-dependent Catecholamine (CA) release, and an anti-hypertensive peptide, but its role includes a modulation of antioxidant and immune defense, epidermal function, and adipose tissue homeostasis. CST influences the cardiocirculatory system acting both indirectly, via the autonomic nervous system, and directly by influencing the basal cardiac function, and the stretch-dependent myocardial performance. It also counteracts the effects of adrenergic stimulation on the heart and protects the myocardium from ischemia/reperfusion (I/R) injury, acting in pre- and postconditioning protection. Conclusions: The knowledge on CST is constantly expanding, thanks to a growing number of human studies that document its involvement in physiological modulation and in many severe diseases, also revealing its applicative potential as a clinical biomarker.

More than 100 years ago, German physician Paul Ehrlich first proposed the concept of selectively delivering “magic bullets” to tumors through targeting agents. The targeting therapy with antibody-drug conjugates (ADCs) and peptide-drug conjugate (PDCs), which are usually composed of monoclonal antibodies or peptides, toxic payloads and cleavage/ noncleavage linkers, has been extensively studied for decades. The conjugates enable selective delivery of cytotoxic payloads to target cells, which results in improved efficacy, reduced systemic toxicity and improved pharmacokinetics (PK)/pharmacodynamics (PD) compared with traditional chemotherapy. PDC and ADC share similar concept, but with vastly different structures and properties. Humanized antibodies introduce high specificity and prolonged half-life, while small molecule weight peptides exhibit higher drug loading and enhanced tissue penetration capacity, and the flexible linear or cyclic peptides are also modified more easily. In this review, the principles of design, synthesis approaches and the latest advances of PDCs are summarized.

Background: Diabetic nephropathy is one of the most important complications in patients with diabetes mellitus. Main steps crucial for the pathogenesis of diabetic nephropathy involve amongst others the modulation of cell signaling via AMP-activated kinase (AMPK) and mammalian target of rapamycin (mTOR), reactive oxygen generation, and endoplasmic reticulum stress under diabetic or hyperglycemic conditions. These processes mediate increased loss of renal cells, such as podocytes, which consequentially leads to renal damage and loss of renal functions, such as structural integrity and glomerular filtration in diabetic nephropathy. The anti-diabetic drug metformin has been widely used for pharmacotherapeutic treatment of patients with diabetes mellitus. Besides its anti-diabetic actions, recent studies revealed additional nephroprotective effects of metformin in vitro and in vivo. Metformin was found to diminish apoptosis in different experimental renal settings. Moreover, it was shown to reduce albuminuria in diabetic rats as well as in patients with type 2 diabetes mellitus. These effects were demonstrated to be mediated via the AMPK/mTOR signaling axis. These data indicate beneficial and renoprotective effects of metformin in diabetic nephropathy. Objective: In this review, we will summarize the latest findings regarding the nephroprotective impact of metformin in vitro and in vivo. Moreover, we will depict and discuss the therapeutic potential of this drug for the treatment of diabetic nephropathy.

Background: Therapeutic angiogenesis is a clinical intervention for controlled stimulation and augmentation of neovascularisation in ischemic tissues. Conventional therapeutic techniques involve proangiogenic factor based induction of host tissue angiogenesis. In this review, we provide a holistic idea about therapeutic angiogenesis while specifically highlighting the role of proangiogenic factors as growth factors, peptides, small molecules and polysaccharides in tissue neovascularisation. Methods: A detailed search of peer-reviewed literature was carried out with prime focus on therapeutic angiogenesis and proangiogenic factors. The content of each literature reviewed in this paper was qualitatively analysed for particulars and relevance to the subject of study. This work has been distributed under four broad titles, namely, proangiogenic growth factors, peptides, small molecules and polysaccharides. Also, recent developments pertaining to proangiogenic factors for therapeutic angiogenesis have been detailed. Results: A total of 244 literatures have been reviewed from the bibliographic database to present a conceptual understanding about the importance of proangiogenic factors in revascularisation of ischemic tissues. Conclusion: This review focuses on importance of various proangiogenic factors, with reference to therapeutic angiogenesis. Thorough analysis of clinical data reveals the dearth of a defined system for proangiogenic growth factor delivery. Designing of a biomaterial based paradigm for growth factor therapy, might help in enhancing clinical translation of therapeutic angiogenesis.