Current Drug Targets - Volume 15, Issue 6, 2014

Lanthionine synthetase component C-like protein 2 (LANCL2) is a member of the LANCL protein family, which is broadly expressed throughout the body. LANCL2 is the molecular target of abscisic acid (ABA), a compound with insulin-sensitizing and immune modulatory actions. LANCL2 is required for membrane binding and signaling of ABA in immune cells. Direct binding of ABA to LANCL2 was predicted in silico using molecular modeling approaches and validated experimentally using ligand-binding assays and kinetic surface plasmon resonance studies. The therapeutic potential of the LANCL2 pathway ranges from increasing cellular sensitivity to anticancer drugs, insulin-sensitizing effects and modulating immune and inflammatory responses in the context of immune-mediated and infectious diseases. A case for LANCL2-based drug discovery and development is also illustrated by the anti-inflammatory activity of novel LANCL2 ligands such as NSC61610 against inflammatory bowel disease and influenza-driven inflammation in mice. This review discusses the value of LANCL2 as a novel therapeutic target for the discovery and development of new classes of orally active drugs against chronic metabolic, immune-mediated and infectious diseases.

Hepatic diseases are turning into one of the few diseases that cannot be effectively cured due to some reasons although various receptors existed in the liver. Currently, several passive targeting delivery systems have been used in the drug/gene delivery for the treatment of hepatic diseases. For example, Zinostatin stimalamer (trade name of Smancs®), a drug-polymer conjugate, was launched in Japan in 1994, which treats hepatocellular carcinoma. More improtantly, different measures would be taken in accord to the specified cell that was lesioned or dysfunctioned via interaction between homing ligands and target receptors so as to improve accumulation of drugs in the target cell and to reduce nonspecific toxicity towards other cells or organs. Therefore, it is urgent to design novel delivery systems that physically or chemically grafted homing devices in order to improve the targeting properties of drugs in specific cell sites. From that perspective, the present article highlights recent development of active hepatic targeting drug/gene delivery systems for the treatment of hepatic diseases that were mediated by some kinds of receptors including asialoglycoprotein receptors (ASGP-R), glycyrrhetinic acid receptor (GA-R), glycyrrhizin receptor (GL-R), hyaluronan receptor (HA-R) and so on.

Dipeptidyl peptidase IV (DPP4) is a promising target for the treatment of chronic metabolic type 2 diabetes mellitus (T2D). DPP4 is a highly specific serine protease involved in the regulation and cleavage of two incretin hormones, glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). These incretin hormones are released by the gastrointestinal tract in response to ingestion of food and stimulate insulin secretion and thereby regulate glucose homeostasis with a low risk of hypoglycemia and glucagon secretion. Currently different chemical classes of DPP4 inhibitors are in last-stage of clinical trials and few of them such as sitagliptin, vildagliptin, saxagliptin alogliptin and linagliptin have already been successfully released into market. These drugs have been approved as either monotherapy or combination therapy with other oral hypoglycemic agents such as metformin, pioglitazone, sulfonylurea, glyburide and glibenclamide for the treatment of T2D. Though several clinical trial compounds were discontinued because of severe adverse toxic effects that are associated with other prolyldipeptidases include DPP8 and DPP9. The current review provides an overview of DPP4 and its inhibitors with emphasis on the structure, expression, activity, selectivity and pharmacokinetics information. This review further dwells upon the issues relating to the rational design and development of selective DPP4 inhibitors for the treatment of T2D.

Histone deacetylases are a class of enzymes that play important roles in post translational modifications of histones by deacetylating the lysine residues as well as interacting with various non-histone proteins. This type of enzymes is closely related to oncogenesis and has been proved to be attractive targets for designing novel anti-cancer agents. Over the last 10 years, a large number of HDACs have entered pre-clinical and/or clinical trials. Among these drug candidates, the pan-HDAC inhibitor, panobinostat demonstrated high therapeutic potential as monotherapy and combined therapy in both preclinical models and clinical cancer patients. In this review, we have mainly focused on the recent progress of the clinical studies about panobinostat, and discussed its anti-cancer effects and molecular rationale for the treatment strategies.

Current modalities for osteoarthritis (OA) treatment are partially safe and effective, and only alleviate the disease symptomatology, but do not modify progression and structural changes of the disease. At present, there is no approved safe and effective disease-modifying OA drug (DMOAD) for clinical application. Therefore, there is an urgent need for discovery of DMOAD in order to treat OA. Hopefully, the new DMOADs would also pave the way for better understanding of OA pathophysiology. Given the fact that there is still no adequate remedy that will modify the course of OA, a number of emerging pathways and promising agents with possible DMOAD effect arise targeting cartilage, synovial membrane, and subchondral bone, or using stem cell therapy, and gene therapy. All these methodologies will be described and discussed in this review. Available treatment methodologies for OA are unsatisfactory. In order to properly treat OA in the future, more realistic option will be the use of multiple drugs, instead of single therapy, which is likely to be ineffective in the treatment of such heterogeneous diseases. Which combination of drugs with DMOAD effect will be suitable for the treatment of OA, remains to be determined in future studies.