Current Drug Targets - Volume 18, Issue 14, 2017

Background: Multidrug resistant Gram negative pathogens pose a persistent threat to the health care system and require investigation of new targets and molecules for the development of antibiotics to treat infections caused by MDR bacterial pathogens. Objective: It is essential to work on multidisciplinary approaches and diverse strategies for developing new compounds acting on novel antibacterial targets. N-acetylglucosamine-1-phosphateuridyltransferase/ glucosamine-1-phosphate-acetyltransferase (GlmU) is one such target which is involved in the synthesis of both peptidoglycan and Lipopolysaccharide in Gram negative and Gram positive bacteria making GlmU an attractive target for developing antibacterials. Results: GlmU, as revealed by X- ray crystallographic studies, is made up of two domains connected by α helical arm; the N-terminal uridyltransferase domain resembles a dinucleotide Rossmann fold and the C- terminal acetyltransferase domain adopts a left handed parallel β helix structure. The GlmU molecules are arranged in a trimeric array, the acetyltransferase active site being formed at the junction of adjacent LβH domain. Many potent inhibitors of both the acetyltransferase and uridyltransferase activity of GlmU have been identified. Inhibitors of the acetyltransferase activity of GlmU include nonspecific thiol reactive agents, 2-phenylbenzofurans, arylamines and arylsulfonamides. A aminopiperidine based inhibitor has also been reported to inhibit uridyltransferase activity of hiGlmU. Conclusion: The present review provides an insight of the structure of GlmU and its reported inhibitors which make GlmU a potential target for drug designing. The GlmU is a promising target for drug discovery against Gram negative pathogens and future studies should focus on GlmU for the development of more potent compounds for treating Gram negative infections.

Background: Parasitic infection such as leishmaniasis, a neglected tropical disease, presents a significant global burden which is responsible for high mortality rate especially in less developed countries. Its intracellular nature and disseminated locations of parasite, limited number of chemotherapeutic agents, increasing incidences of resistance to first line drugs and toxicities, pose a great challenge to formulation scientists that have necessitated effective management of leishmanial infection by modulating the delivery of existing drugs. Over the past decade, research on development of alternative treatments such as nanotechnology-based drug delivery systems (nanoparticles, nanosuspensions, liposomes etc.), use of natural products as well as development of antileishmanial vaccine has been extensively investigated. Objective: The present review focuses on different facets of therapeutic strategies, existing miscellaneous drug delivery systems and approaches intended for management, as well as treatment of the infection, with an objective to summarize the current trends and strategies adopted for antileishmanial therapy in a systematic manner. Moreover, the article encloses an eclectic collection of patents allied to new-fangled chemotherapeutics for antileishmanial therapy. Conclusion: The reported miscellaneous novel drug delivery systems along with the diverse approaches are seem to be precise, secure and relatively effective; and in an outcome, could lead to the new track for management of leishmaniasis.

Objective: To review the role of PI3K/AKT/mTOR signalling pathway, and the current and future prospects of targeting PI3Ks for various diseases, like malignant, autoimmune, inflammatory, cardiovascular, neurological disorders etc., laying special emphasis on the inflammatory diseases and associated cellular responses. Background: Recent findings have publicized phosphoinositide-3-kinases (PI3Ks) as novel therapeutic targets, which are also purported to be involved in the complex pathophysiology of inflammatory and various other diseases. They are recognized to participate in the inflammatory cellular responses by modulating the growth, development and proliferation of various immune cells and hence, affect the release of various cytokines and other inflammatory mediators involved in these manifestations. The recent literature relating this pathway with these diseases is highlighted, with a hope, which remains for the progression of PI3K inhibitors in the market as a treatment option. Result: With Idelalisib entering the market for cancer, PI3K/AKT signalling has also gained significance as an investigational target for various diseases, particularly for inflammation. Based on the pharmacological, genetic, and clinical data available, PI3K/AKT signalling can be designated as an outstanding target for their treatment. Conclusion: Further exploration of this pathway may also uncover its involvement in these disorders, which may further contribute to developing the new treatments and can turn out to be an innovative brainwave in the field of experimental and clinical pharmacology in future.

Background: Rheumatoid arthritis (RA) and osteoarthritis (OA) are widespread rheumatic diseases characterized by persistent inflammation and joint destruction. Hydrogen sulfide (H2S) is an endogenous gas with important physiologic functions in the brain, vasculature and other organs. Recent studies have found H2S to be a mediator in inflammatory joint diseases. Objective: This review summarizes the recent literature in this area highlighting relevant developments. Conclusions: Several authors have found that H2S exhibited anti-inflammatory, anti-catabolic and/or anti-oxidant effects in rodent models of acute arthritis and in in vitro models using human synoviocytes and articular chondrocytes from RA and OA tissues. The earliest studies used fast-dissolving salts, such as NaSH, but GYY4137, which produces H2S more physiologically, shortly appeared. More recently still, new H2S-forming compounds that target mitochondria have been synthesized. These compounds open exciting opportunities for investigating the role of H2S in cell bioenergetics, typically altered in arthritides. Positive results have also been obtained when H2S is administered as a sulphurous water bath, an option meriting further study. These findings suggest that exogenous supplementation of H2S may provide a viable therapeutic option for these diseases, particularly in OA.

Background: The present era is fast experiencing rapid innovation in the genome-editing technology. CRISPR Cas9-mediated targeted genetic manipulation is an easy, cost-effective and scalable method. As a result, it can be used for a broad range of targeted genome engineering. Objective: The main objective of the present review is to highlight the structural signature, classification, its mechanism and application from basic science to medicine and future challenges for this genome editing tool kit. Results: The present review provides a brief description of the recent development of CRISPR-Cas9 genome editing technology. We discuss the paradigms shift for this next generation genome editing technology, CRISPR. The CRISPR structural significance, classification and its different applications are also being discussed. We portray the future challenges for this extraordinary genome in vivo editing tool. We also highlight the role of CRISPR genome editing in curing many diseases. Conclusion: Scientists and researchers are constantly looking one genome editing tool that is competent, simple and low-cost assembly of nucleases. It can target any particular site without any off-target mutations in the genome. The CRISPR-Cas9 has all of the above characteristics. The genome engineering technology may be a strong and inspiring technology meant for the next generation of drug development.

Background: Obesity was traditionally considered as a positive regulator on the strength of bone. With the in-depth study, obesity is considered as a major risk factor for osteoporosis. Some proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) are the factors that fat uses to negatively regulate bone metabolism. Objective: This review was aimed to summarize and critically discuss the convincing evidence for the therapeutic effectiveness of pro-inflammatory cytokines for the treatment of obesity-related bone disorders. Results: Obese people and animals show a higher level of serum TNF-α and IL-6, which are produced by macrophages derived from adipose tissue. These pro-inflammatory cytokines regulate the proliferation and apoptosis of adipocyte, promote lipolysis, inhibit lipid synthesis and decrease blood lipids through autocrine and paracrine way. On the other hand, TNF-α and IL-6 regulate bone metabolism through the endocrine way. Several reports suggest that TNF-α is a negative regulator of osteoblast at some stages of differentiation and positively regulates osteoclast proliferation and differentiation. In contrast, IL-6 influences osteoblasts and osteoclasts through complex mechanisms, which reflect dual effects. In addition, TNF-α and IL-6 may regulate bone metabolism indirectly by regulating adiponectin and leptin released from adipocytes. Conclusion: In this review, we first summarize the role of TNF-α and IL-6 in lipid and bone metabolisms. We further discuss how TNF-α and IL-6 regulate the communication between fat and bone, and their pathological roles in obesity-related bone disorders. Lastly, we discuss the possibility of using pro-inflammatory signaling pathway as a therapeutic target to develop drug for obesity-related bone disorders.

Background: Protein farnesyltransferase (PFT) inhibitors have emerged as a potent target for the malaria treatment caused by the Plasmodium falciparum (Pf) parasite. Objective: To explore the various scaffolds which are active against Pf-PFT target. Result: Seven inhibitor scaffolds based on ethylenediamine, peptidomimetic, benzophenone, benzamide, tetrahydroquinoline, naphthyridine and oxy-tetrahydroquinoline, have been developed till date. Conclusion: It is concluded that naphthyridine based drugs are the most promising one. Furthermore, introducing the hydrophobic molecules like isoprenyl groups to a protein or a chemical compound facilitate protein-protein and protein-membrane interactions thereby makes them good candidates as new therapeutics. The future research should focus on the disease rather than the infection and the dynamics of its transmission; this will bring a new vision about the disease.