Exploring antibiofilm potential of some new imidazole analogs against C. albicans: synthesis, antifungal activity, molecular docking and molecular dynamics studies.

A series of 1, 2, 4, 5-tetrasubstituted imidazole derivatives were synthesized and their antibiofilm potential against Candida albicans was evaluated in vitro. Two of the synthesized derivatives 5e (IC50 = 25 µg/mL) and 5m (IC50 = 6 µg/mL),displayed better antifungal and antibiofilm potential than the standard drug Fluconazole (IC50 = 40 µg/mL) against C. albicans. Based on the in vitro results, we escalated the real time polymerase chain reaction (RT-PCR) analysis to gain knowledge of the enzymes expressed in the generation and maintenance of biofilms and the mechanism of biofilm inhibition by the synthesized analogues. We then investigated the possible interactions of the synthesized compounds in inhibiting agglutinin-like proteins, namely Als3, Als4 and Als6 were prominently down-regulated using in-silico molecular docking analysis against the previously available crystal structure of Als3 and constructed structure of Als4 and Als6 using the SWISS-MODEL server. The stability and energy of the agglutinin-like proteins-ligand complexes were evaluated using molecular dynamics simulations (MDS). According to the 100 ns MDS, all the compounds remained stable, formed a maximum of 3, and on average 2 hydrogen bonds, and Gibb's free energy landscape analysis suggested greater affinity of the compounds 5e and 5m toward Als4 protein.Communicated by Ramaswamy H. Sarma.

Insilico structure based drug design approach to find potential hits in ventilator-associated pneumonia caused by Pseudomonas aeruginosa.

Tetraacyldisaccharide 4'-kinase (LpxK) is the prime enzyme responsible for the biosynthesis of lipid A. LpxK is a key antibacterial drug target, but it is less exploitation in Pseudomonas aeruginosa and other bacterial species limits its therapeutic use. Pseudomonas aeruginosa is responsible for severe infections like pneumonia and urinary tract infections. The precautionary measures of Pseudomonas aeruginosa infections are decisive as it results in extensive drug resistance, systemic bacteremia, and ventilator-associated pneumonia. The current rational approach highlights exploiting the use of computer-aided drug design approaches to counter Pseudomonas aeruginosa specific LpxK. The various approaches used were exploring the metabolic pathway database (Metacyc), drug target validation using DEG, protein modeling, ligand docking, e-pharmacophore assisted virtual screening, physicochemical and Toxicity profile prediction studies, and molecular simulations in spotting out novel potential hits compounds. The virtual hits which have highly ranked in the study were STOCK4S-16119, STOCK1S -60869, STOCK6S -43621, STOCK6S -3328, and STOCKS-39892 which can act as a scaffold for the establishment of new hits against LpxK and can result in control of Pseudomonas aeruginosa infectivity.

Efficient gene transfection to lung cancer cells via Folate-PEI-Sorbitol gene transporter.

Lung cancer is known to be one of the fatal diseases in the world and is experiencing treatment difficulties. Many treatments have been discovered and implemented, but death rate of patients with lung cancer continues to remain high. Current treatments for cancer such as chemotherapy, immunotherapy, and radiotherapy have shown considerable results, yet they are accompanied by side effects. One effective method for reducing the cytotoxicity of these treatments is via the use of a nanoparticle-mediated siRNA delivery strategy with selective silencing effects and non-viral vectors. In this study, a folate (FA) moiety ligand-conjugated poly(sorbitol-co-PEI)-based gene transporter was designed by combining low-molecular weight polyethyleneimine (LMW PEI) and D-sorbitol with FA to form FPS. Since folate receptors are commonly overexpressed in various cancer cells, folate-conjugated nanoparticles may be more effectively delivered to selective cancer cells. Additionally, siOPA1 was used to induce apoptosis through mitochondrial fusion. The OPA1 protein stability level is important for maintaining normal mitochondrial cristae structure and function, conserving the inner membrane structure, and protecting cells from apoptosis. Consequently, when FPS/siOPA1 was used for lung cancer in-vitro and in-vivo, it improved cell viability and cellular uptake.

Development of novel, biocompatible, polyester amines for microglia-targeting gene delivery.

Recent progress in personalized medicine and gene delivery has created exciting opportunities in therapeutics for central nervous system (CNS) disorders. Despite the interest in gene-based therapies, successful delivery of nucleic acids for treatment of CNS disorders faces major challenges. Here we report the facile synthesis of a novel, biodegradable, microglia-targeting polyester amine (PEA) carrier based on hydrophilic triethylene glycol dimethacrylate (TG) and low-molecular weight polyethylenimine (LMW-PEI). This nanocarrier, TG-branched PEI (TGP), successfully condensed double-stranded DNA into a size smaller than 200 nm. TGP nanoplexes were nontoxic in primary mixed glial cells and showed elevated transfection efficiency compared with PEI-25K and lipofector-EZ. After intrathecal and intracranial administration, PEA nanoplexes delivered genes specifically to microglia in the spinal cord and brain, respectively, proposing TGP as a novel microglia-specific gene delivery nanocarrier. The microglia-specific targeting of the TGP nanocarrier offers a new therapeutic strategy to modulate CNS disorders involving aberrant microglia activation while minimizing off-target side effects.

Insights of tankyrases: A novel target for drug discovery.

Tankyrases are the group of enzymes belonging to a class of Poly (ADP-ribose) polymerase (PARP) recently named ADP-ribosyltransferase (ARTD). The two isoforms of tankyrase i.e. tankyrase1 (TNKS1) and tankyrase2 (TNKS2) were abundantly expressed in various biological functions in telomere regulation, Wnt/ß-catenin signaling pathway, viral replication, endogenous hormone regulation, glucose transport, cherubism disease, erectile dysfunction, and apoptosis. The structural analysis, mechanistic information, in vitro and in vivo studies led identification and development of several classes of tankyrase inhibitors under clinical phases. In the nutshell, this review will drive future research on tankyrase as it enlighten the structural and functional features of TNKS 1 and TNKS 2, different classes of inhibitors with their structure-activity relationship studies, molecular modeling studies, as well as past, current and future perspective of the different class of tankyrase inhibitors.

Synthesis and biological activity of structurally diverse phthalazine derivatives: A systematic review.

Phthalazine, a structurally and pharmacologically versatile nitrogen-containing heterocycle, has gained more attention from medicinal chemists in the design and synthesis of novel drugs owing to its pharmacological potential. In particular, phthalazine scaffold appeared as a pharmacophoric feature numerous drugs exhibiting pharmacological activities, in particular, antidiabetic, anticancer, antihypertensive, antithrombotic, anti-inflammatory, analgesic, antidepressant and antimicrobial activities. This review presents a summary of updated and detailed information on phthalazine as illustrated in both patented and non-patented literature. The reported literature have described the optimal pharmacological characteristics of phthalazine derivatives and highlighted the applicability of phthalazine, as potent scaffold in drug discovery.

Sugar alcohol-based polymeric gene carriers: Synthesis, properties and gene therapy applications.

Advances in the field of nanomedicine have led to the development of various gene carriers with desirable cellular responses. However, unfavorable stability and physicochemical properties have hindered their applications in vivo. Therefore, multifunctional, smart nanocarriers with unique properties to overcome such drawbacks are needed. Among them, sugar alcohol-based nanoparticle with abundant surface chemistry, numerous hydroxyl groups, acceptable biocompatibility and biodegradable property are considered as the recent additions to the growing list of non-viral vectors. In this review, we present some of the major advances in our laboratory in developing sugar-based polymers as non-viral gene delivery vectors to treat various diseases. We also discuss some of the open questions in this field. STATEMENT OF SIGNIFICANCE: Recently, the development of sugar alcohol-based polymers conjugated with polyethylenimine (PEI) has attracted tremendous interest as gene delivery vectors. First, the natural backbone of polymers with their numerous hydroxyl groups display a wide range of hyperosmotic properties and can thereby enhance the cellular uptake of genetic materials via receptor-mediated endocytosis. Second, conjugation of a PEI backbone with sugar alcohols via Michael addition contributes to buffering capacity and thereby the proton sponge effect. Last, sugar alcohol based gene delivery systems improves therapeutic efficacy both in vitro and in vivo.

Molecular docking, pharmacophore based virtual screening and molecular dynamics studies towards the identification of potential leads for the management of H. pylori.

The enzyme pantothenate synthetase panC is one of the potential new antimicrobial drug targets, but it is poorly characterized in H. pylori. H. pylori infection can cause gastric cancer and the management of H. pylori infection is crucial in various gastric ulcers and gastric cancer. The current study describes the use of innovative drug discovery and design approaches like comparative metabolic pathway analysis (Metacyc), exploration of database of essential genes (DEG), homology modelling, pharmacophore based virtual screening, ADMET studies and molecular dynamics simulations in identifying potential lead compounds for the H. pylori specific panC. The top ranked virtual hits STOCK1N-60270, STOCK1N-63040, STOCK1N-44424 and STOCK1N-63231 can act as templates for synthesis of new H. pylori inhibitors and they hold a promise in the management of gastric cancers caused by H. pylori.

Biodegradable Polymeric Nanocarrier-Based Immunotherapy in Hepatitis Vaccination.

Various commercial vaccines are used for immunization against hepatitis B. However, these immunotherapeutic vaccines require invasive administration, which can induce side effects, and require multiple shots to elicit an immune response, limiting their efficacy. Compared to traditional hepatitis B vaccines, polymer nanoparticles have more advantageous inherent properties as vaccine delivery carriers, providing increased stability of encapsulated antigen, the possibility of single-shot immunotherapy, and the capability of mucosal administration, which allows various routes of vaccination. In this review, we present up-to-date information on the potential of a biodegradable nanoparticle-based delivery system in treating hepatitis B. We also discuss the application of nanoparticles in various vaccines and highlighted strategies for eliciting an appropriate immune response.

Targeted Delivery of siRNA Therapeutics using Ligand Mediated Biodegradable Polymeric Nanocarriers.

BACKGROUND: Cancer poses a major public health issue, is linked with high mortality rates across the world, and shows a strong interplay between genetic and environmental factors. To date, common therapeutics, including chemotherapy, immunotherapy, and radiotherapy, have made significant contributions to cancer treatment, although diverse obstacles for achieving the permanent "magic bullet" cure have remained. Recently, various anticancer therapeutic agents designed to overcome the limitations of these conventional cancer treatments have received considerable attention. One of these promising and novel agents is the siRNA delivery system; however, poor cellular uptake and altered siRNA stability in physiological environments have limited its use in clinical trials. Therefore, developing the ideal siRNA delivery system with low cytotoxicity, improved siRNA stability in the body's circulation, and prevention of its rapid clearance from bodily fluids, is rapidly emerging as an innovative therapeutic strategy to combat cancer. Moreover, active targeting using ligand moieties which bind to over-expressed receptors on the surface of cancer cells would enhance the therapeutic efficiency of siRNA. CONCLUSION: In this review, we provide 1) an overview of the non-viral carrier associated with siRNA delivery for cancer treatment, and 2) a description of the five major cancer-targeting ligands.

Sugar-based gene delivery systems: Current knowledge and new perspectives.

Carbohydrates, one of the most abundant natural compounds and key participants in many biological processes, are relevant in medical and industrial fields. In comparison with synthetic polymers, carbohydrates are biocompatible and have intrinsic targeting properties, enabling them to interact with cell-surface receptors. Among the different carbohydrates, polysaccharides are naturally occurring biological molecules with tremendous potential for biomedical applications. The physicochemical properties of these polysaccharide based nanoparticles, such as excellent biocompatibility, surface charge to interact with nucleic acids, low toxicity and cost effectiveness make them superior carriers for nanomedicine. In addition to variety of physicochemical properties, polysaccharides allow the great ease of chemical modification which enables the preparation of wide range of nanoparticles. In this review, we present the state-of-the-art information on the potential of polysaccharides-based polymers as non-viral gene delivery vectors in treating various diseases. Then, we discuss the chemical modification and structure/property relationship of carbohydrates.

Bacterial Peptide Deformylase Inhibition of Tetrazole-Substituted Biaryl Acid Analogs: Synthesis, Biological Evaluations, and Molecular Docking Study.

The synthesis and screening of tetrazole-substituted biaryl acid analogs 7a-l as bacterial peptide deformylase (PDF) enzyme inhibitors is reported. The compounds 7e (IC50 value = 5.50 µM) and 7g (IC50 value = 7.25 µM) showed good PDF inhibition activity. The compounds 7e (MIC range = 10.75-11.66 µg/mL) and 7g (MIC range = 8.91-12.83 µg/mL) also showed potent antibacterial activity when compared with the standard ciprofloxacin (MIC range = 25-50 µg/mL). Thus, the active derivatives were not only potent PDF enzyme inhibitors but also efficient antibacterial agents. In order to gain more insight into the binding mode of the compounds with the PDF enzyme, the most active compounds 7e and 7g, the moderately active compound 7k, and the least active compound 7h were docked against the PDF enzyme of Escherichia coli. The docking study of the most active compounds 7e and 7g against the PDF enzyme exhibited good binding properties. Hence, we believe our synthesized compounds 7a-l could serve as reservoir for bacterial PDF inhibitor development.

Biphenyl tetrazole-thiazolidinediones as novel bacterial peptide deformylase inhibitors: Synthesis, biological evaluations and molecular docking study.

Herein, we report the synthesis and screening of biphenyl tetrazole-thiazolidinediones 14(a-j) as bacterial Peptide deformylase (PDF) enzyme inhibitors. The compounds 14b (IC50 value=16.25µM), 14c (IC50 value=18.00µM) and 14h (IC50 value=17.25µM) had shown good PDF inhibition activity. The compounds 14b (MIC range=20.75-35.41µg/mL), 14c (MIC range=19.41-26.00µg/mL) and 14d (MIC range=8.41-8.58µg/mL) had also shown potent antibacterial activity when compared with standard ciprofloxacin (MIC range=25-50µg/mL). Thus, the active derivatives were not only potent PDF inhibitors but also efficient antibacterial agents. In order to gain more insight on the binding mode of the compounds with PDF enzyme, the synthesized compounds 14(a-j) were docked against PDF enzyme of E. coli and compounds exhibited good binding properties. The results suggest that this class of compounds have been potential for development and use in a future as antibacterial drugs.

Efficient gene transfection to liver cells via the cellular regulation of a multifunctional polylactitol-based gene transporter.

In recent years, the introduction of non-viral gene transfer systems for the treatment of inherited and acquired liver diseases has attracted a lot of attention. To facilitate liver-directed gene delivery, a liver cell targeting strategy and a intracellular control of gene trafficking for the design of an ideal non-viral gene delivery system are crucial and a great challenge. In order to meet these needs, a new multifunctional gene carrier, the polylactitol-based gene transporter (PLT), was prepared by crosslinking low molecular weight polyethylenimine (LMW PEI) with lactitol diacrylate (LDA) composed of d-galactose and d-sorbitol. These provide synergistic effects that increase cellular uptake, result in liver cell targeting and a rapid release of the gene from the endosome, because the hyperosmotic property of the polysorbitol part selectively stimulates caveolae-mediated endocytosis, the polygalactose part provides liver cell targeting ability and the PEI part assists in the rapid endosomal escape of the gene due to its proton sponge effect. With these unique multifunctions, PLT/DNA nanocomplexes showed low cytotoxicity, high transfection efficiency, liver cell targeting in vitro and in vivo, and a selective transition of the cellular uptake pathway into the caveolae-mediated endocytosis avoiding lysosomal degradation. PLT was confirmed as a safe and efficient vector, highlighting a potential candidate for targeted gene therapy in hepatic diseases.

Correction: Efficient gene transfection to liver cells via the cellular regulation of a multifunctional polylactitol-based gene transporter.

Correction for 'Efficient gene transfection to liver cells via the cellular regulation of a multifunctional polylactitol-based gene transporter' by Young-Dong Kim et al., J. Mater. Chem. B, 2016, 4, 2208-2218.

Gene therapy for bone tissue engineering.

Gene therapy holds a great promise and has been extensively investigated to improve bone formation and regeneration therapies in bone tissue engineering. A variety of osteogenic genes can be delivered by combining different vectors (viral or non-viral), scaffolds and delivery methodologies. Ex vivo & in vivo gene enhanced tissue engineering approaches have led to successful osteogenic differentiation and bone formation. In this article, we review recent advances of gene therapy-based bone tissue engineering discussing strengths and weaknesses of various strategies as well as general overview of gene therapy.

Image-Guided Nanoparticle-Based siRNA Delivery for Cancer Therapy.

With the discovery of RNA interference technology, small-interfering RNA (siRNA) has emerged as new powerful tool for gene therapy because of its high targeting specificity and selectivity. However, one of the limitations to successful gene therapy is the inability to monitor delivery of genes and therapeutic responses at the targeted site. Hence, a combinatorial approach of gene therapy with molecular imaging has been crucial in optimizing gene therapy. Recent advances in nanotechnology have made tremendous efforts to develop multifunctional nanoparticles that contain imaging and therapeutic agents together for image-guided therapy. The nanoparticles serve as contrast agents in imaging for disease detection with simultaneous delivery of therapeutics to cure the diseases. The therapy also helps to monitor the drug accumulation and assimilation in the body, thereby facilitating the evaluation of treatment effects. Here, we present an overview of polymer and lipid-based carriers for siRNA delivery, along with imaging agents as image guided therapy, in the treatment of breast, lung, liver, ovarian, cervical, and prostate cancers.

Nanoparticle-mediated delivery of siRNA for effective lung cancer therapy.

Lung cancer is one of the most lethal diseases worldwide, and the survival rate is less than 15% even after the treatment. Unfortunately, chemotherapeutic treatments for lung cancer are accompanied by severe side effects, lack of selectivity and multidrug resistance. In order to overcome the limitations of conventional chemotherapy, nanoparticle-mediated RNA interference drugs represent a potential new approach due to selective silencing effect of oncogenes and multidrug resistance related genes. In this review, we provide recent advancements on nanoparticle-mediated siRNA delivery strategies including lipid system, polymeric system and rigid nanoparticles for lung cancer therapies. Importantly, codelivery of siRNA with conventional anticancer drugs and recent theranostic agents that offer great potential for lung cancer therapy is covered.

Aerosol delivery of beclin1 enhanced the anti-tumor effect of radiation in the lungs of K-rasLA1 mice.

Radiotherapy alone has several limitations for treating lung cancer. Inhalation, a non-invasive approach for direct delivery of therapeutic agents to the lung, may help to enhance the therapeutic efficacy of radiation. Up-regulating beclin1, known as a tumor suppressor gene that plays a major role in autophagy, may sensitize tumors and lead to tumor regression in lungs of K-ras(LA1) lung cancer model mice. To minimize the side-effects of radiotherapy, fractionated exposures (five times, 24-h interval) with low dose (2 Gy) of radiation to the restricted area (thorax, 2 cm) were conducted. After sensitizing the lungs with radiation, beclin1, complexed with a nano-sized biodegradable poly(ester amine), was prepared and delivered into the murine lung via aerosol three times/week for four weeks. In a histopathological analysis, animals treated with beclin1 and radiation showed highly significant tumor regression and low progression to adenocarcinoma. An increase in the number of autophagic vacuoles and secondary lysosomes was detected. Dissociation of beclin1-bcl2 stimulated autophagy activation and showed a synergistic anti-tumor effect by inhibiting the Akt-mTOR pathway, cell proliferation and angiogenesis. The combination of radiation with non-invasive aerosol delivery of beclin1 may provide a prospect for developing novel therapy regimens applicable in clinics.

Accelerated gene transfer through a polysorbitol-based transporter mechanism.

Here we report an accelerated gene transfer through a polysorbitol-based osmotically active transporter (PSOAT) that shows several surprising results through interesting mechanisms. The nano-sized and well-complexed PSOAT/DNA particles are less toxic, stable at serum and show no aggregation after lyophilization due to their polysorbitol backbone. The transfection is remarkably accelerated both in vitro and in vivo, presumably due to a transporter mechanism of PSOAT in spite of possibility of reduction of transfection by many hydroxyl groups in the transporter. PSOAT possesses a transporter mechanism owing to its polysorbitol backbone, which enhances cellular uptake by exerting polysorbitol transporter activity, thus accelerates gene transfer to cells because transfection ability of PSOAT is drastically reduced in the presence of a cyclooxygenase (COX)-2-specific inhibitor, which we have reported as an inhibitor of the transporter to cells. Moreover, the gene expression is found to be enhanced by hyperosmotic activity and buffering capacity due to polysorbitol and polyethylenimine backbone of PSOAT, respectively. The polysorbitol in PSOAT having polyvalency showed more efficiency in accelerating gene transfer capability than monovalent sorbitol. The above interesting mechanisms display PSOAT as a remarkably potential system to deliver therapeutic (small interfering RNA) and diagnostic agents for effective treatment of cancer.