2Receptor Specific Ligand conjugated Nanocarriers: an Effective Strategy for Targeted Therapy of Tuberculosis

2021 ◽  
Vol 19 ◽  
Author(s):  
Pratiksha Prabhu ◽  
Trinette Fernandes ◽  
Mansi Damani ◽  
Pramila Chaubey ◽  
Shridhar Narayanan ◽  
...  
Keyword(s):  
Mycolic Acid ◽  
Wall Structure ◽  
Epithelial Surface ◽  
Antitubercular Drugs ◽  
Drug Molecules ◽  
Effective Delivery ◽  
Alveolar Tissue ◽  
Reduced Toxicity ◽  
Unique Cell ◽  
Cellular Components

: Tuberculosis (TB) is an ancient chronic disease caused by the bacillus Mycobacterium tuberculosis, which has affected mankind for more than 4,000 years. Compliance with the standard conventional treatment can assure recovery from tuberculosis, but emergence of drug resistant strains pose a great challenge for effective management of tuberculosis. The process of discovery and development of new therapeutic entities with better specificity and efficacy is unpredictable and time consuming. Hence, delivery of pre-existing drugs with improved targetability is the need of the hour. Enhanced delivery and targetability can ascertain improved bioavailability, reduced toxicity, decreased frequency of dosing and therefore better patient compliance. Nanoformulations are being explored for effective delivery of therapeutic agents, however optimum specificity is not guaranteed. In order to achieve specificity, ligands specific to receptors or cellular components of macrophage and Mycobacteria can be conjugatedto nanocarriers. This approach can improve localization of existing drug molecules at the intramacrophageal site where the parasites reside, improve targeting to the unique cell wall structure of Mycobacterium or improve adhesion to epithelial surface of intestine or alveolar tissue (lectins). Present review focuses on the investigation of various ligands like Mannose, Mycolic acid, Lectin, Aptamers etc. installed nanocarriers that are being envisaged for targeting antitubercular drugs.

Current Nanotechnological Approaches for an Effective Delivery of Bioactive Drug Molecules to Overcome Drug Resistance Tuberculosis

2015 ◽  
Vol 21 (22) ◽  
pp. 3076-3089 ◽  
Author(s):  
Tarun Garg ◽  
Goutam Rath ◽  
Rayasa Murthy ◽  
Umesh Gupta ◽  
Palakkod Vatsala ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Drug Molecules ◽  
Effective Delivery

Lead Molecule Prediction and Characterization for Designing MERS-CoV 3C-like Protease Inhibitors: An In silico Approach

2018 ◽  
Vol 15 (1) ◽  
pp. 82-88 ◽  
Author(s):  
Md. Mostafijur Rahman ◽  
Md. Bayejid Hosen ◽  
M. Zakir Hossain Howlader ◽  
Yearul Kabir
Keyword(s):  
Binding Energy ◽  
Middle East ◽  
Virtual Screening ◽  
In Silico ◽  
Screening Method ◽  
Middle East Respiratory Syndrome ◽  
Cytochrome P450 Enzymes ◽  
Drug Molecules ◽  
Essential Enzyme ◽  
Reduced Toxicity

Background: 3C-like protease also called the main protease is an essential enzyme for the completion of the life cycle of Middle East Respiratory Syndrome Coronavirus. In our study we predicted compounds which are capable of inhibiting 3C-like protease, and thus inhibit the lifecycle of Middle East Respiratory Syndrome Coronavirus using in silico methods. </P><P> Methods: Lead like compounds and drug molecules which are capable of inhibiting 3C-like protease was identified by structure-based virtual screening and ligand-based virtual screening method. Further, the compounds were validated through absorption, distribution, metabolism and excretion filtering. Results: Based on binding energy, ADME properties, and toxicology analysis, we finally selected 3 compounds from structure-based virtual screening (ZINC ID: 75121653, 41131653, and 67266079) having binding energy -7.12, -7.1 and -7.08 Kcal/mol, respectively and 5 compounds from ligandbased virtual screening (ZINC ID: 05576502, 47654332, 04829153, 86434515 and 25626324) having binding energy -49.8, -54.9, -65.6, -61.1 and -66.7 Kcal/mol respectively. All these compounds have good ADME profile and reduced toxicity. Among eight compounds, one is soluble in water and remaining 7 compounds are highly soluble in water. All compounds have bioavailability 0.55 on the scale of 0 to 1. Among the 5 compounds from structure-based virtual screening, 2 compounds showed leadlikeness. All the compounds showed no inhibition of cytochrome P450 enzymes, no blood-brain barrier permeability and no toxic structure in medicinal chemistry profile. All the compounds are not a substrate of P-glycoprotein. Our predicted compounds may be capable of inhibiting 3C-like protease but need some further validation in wet lab.

Combinatorial Design of Molecule using Activity-Linked Substructural Topological Information as Applied to Antitubercular Compounds

2018 ◽  
Vol 15 (1) ◽  
pp. 67-81 ◽  
Author(s):  
Chandan Raychaudhury ◽  
Md. Imbesat Hassan Rizvi ◽  
Debnath Pal
Keyword(s):  
Biological Activities ◽  
Combinatorial Design ◽  
Combinatorial Structure ◽  
Potential Drug ◽  
Structure Generation ◽  
Topological Information ◽  
Active Compounds ◽  
Antitubercular Drugs ◽  
Topological Distance ◽  
Drug Molecules

Background: Generating a large number of compounds using combinatorial methods increases the possibility of finding novel bioactive compounds. Although some combinatorial structure generation algorithms are available, any method for generating structures from activity-linked substructural topological information is not yet reported. Objective: To develop a method using graph-theoretical techniques for generating structures of antitubercular compounds combinatorially from activity-linked substructural topological information, predict activity and prioritize and screen potential drug candidates. </P><P> Methods: Activity related vertices are identified from datasets composed of both active and inactive or, differently active compounds and structures are generated combinatorially using the topological distance distribution associated with those vertices. Biological activities are predicted using topological distance based vertex indices and a rule based method. Generated structures are prioritized using a newly defined Molecular Priority Score (MPS). Results: Studies considering a series of Acid Alkyl Ester (AAE) compounds and three known antitubercular drugs show that active compounds can be generated from substructural information of other active compounds for all these classes of compounds. Activity predictions show high level of success rate and a number of highly active AAE compounds produced high MPS score indicating that MPS score may help prioritize and screen potential drug molecules. A possible relation of this work with scaffold hopping and inverse Quantitative Structure-Activity Relationship (iQSAR) problem has also been discussed. The proposed method seems to hold promise for discovering novel therapeutic candidates for combating Tuberculosis and may be useful for discovering novel drug molecules for the treatment of other diseases as well.

scholarly journals Characterization of LtsA from Rhodococcus erythropolis, an Enzyme with Glutamine Amidotransferase Activity

2005 ◽  
Vol 187 (8) ◽  
pp. 2582-2591 ◽  
Author(s):  
Yasuo Mitani ◽  
XianYing Meng ◽  
Yoichi Kamagata ◽  
Tomohiro Tamura
Keyword(s):  
Cell Wall ◽  
Culture Media ◽  
Rhodococcus Erythropolis ◽  
Mycolic Acid ◽  
Site Directed Mutagenesis ◽  
Host Cells ◽  
Wall Structure ◽  
Synthetase Activity ◽  
Glutamine Amidotransferase ◽  
Glutaminase Activity

ABSTRACT The nocardioform actinomycete Rhodococcus erythropolis has a characteristic cell wall structure. The cell wall is composed of arabinogalactan and mycolic acid and is highly resistant to the cell wall-lytic activity of lysozyme (muramidase). In order to improve the isolation of recombinant proteins from R. erythropolis host cells (N. Nakashima and T. Tamura, Biotechnol. Bioeng. 86:136-148, 2004), we isolated two mutants, L-65 and L-88, which are susceptible to lysozyme treatment. The lysozyme sensitivity of the mutants was complemented by expression of Corynebacterium glutamicum ltsA, which codes for an enzyme with glutamine amidotransferase activity that results from coupling of two reactions (a glutaminase activity and a synthetase activity). The lysozyme sensitivity of the mutants was also complemented by ltsA homologues from Bacillus subtilis and Mycobacterium tuberculosis, but the homologues from Streptomyces coelicolor and Escherichia coli did not complement the sensitivity. This result suggests that only certain LtsA homologues can confer lysozyme resistance. Wild-type recombinant LtsA from R. erythropolis showed glutaminase activity, but the LtsA enzymes from the L-88 and L-65 mutants displayed drastically reduced activity. Interestingly, an ltsA disruptant mutant, which expressed the mutated LtsA, changed from lysozyme sensitive to lysozyme resistant when NH4Cl was added into the culture media. The glutaminase activity of the LtsA mutants inactivated by site-directed mutagenesis was also restored by addition of NH4Cl, indicating that NH3 can be used as an amide donor molecule. Taken together, these results suggest that LtsA is critically involved in mediating lysozyme resistance in R. erythropolis cells.

Effective delivery of immunosuppressive drug molecules by silica coated iron oxide nanoparticles

2016 ◽  
Vol 142 ◽  
pp. 290-296 ◽  
Author(s):  
Jangsun Hwang ◽  
Eunwon Lee ◽  
Jieun Kim ◽  
Youngmin Seo ◽  
Kwan Hong Lee ◽  
...  
Keyword(s):  
Iron Oxide ◽  
Iron Oxide Nanoparticles ◽  
Immunosuppressive Drug ◽  
Oxide Nanoparticles ◽  
Drug Molecules ◽  
Effective Delivery

CURRENTLY USED ANTI-TUBERCULAR AGENTS, THEIR ANALOGUES AND RECENTLY DEVELOPED DRUGS

INDIAN DRUGS ◽  
2012 ◽  
Vol 49 (07) ◽  
pp. 5-19
Author(s):  
A Mohammad ◽  
Keyword(s):  
Antimicrobial Activity ◽  
Side Effects ◽  
Multidrug Resistant ◽  
Drug Resistant ◽  
Duration Of Treatment ◽  
Duration Of Therapy ◽  
Drug Molecules ◽  
Prolonged Duration ◽  
Resistant Strains ◽  
Reduced Toxicity

Tuberculosis (TB) is one of most prevailing diseases, responsible for the morbidity and mortality of a large number of populations worldwide. Traditionally, it has relied on a limited number of drugs such as isoniazid, rifampicin, ethambutol, streptomycin, ethionamide and pyrazinamide. However, many of these drugs have different disadvantages such as prolonged duration of treatment, host toxicity and ineffectiveness against resistant strains. This has motivated the search of newer drug molecules, capable of rapid mycobactericidal action with shortened duration of therapy, reduced toxicity and enhanced activity against multidrug resistant strains. These observations have been guiding for the currently used and newly developed anti-tubercular agents that possess potent antimicrobial activity and their side effects, activity against multi drug resistant Mycobacterium, and also in patients co-infected with HIV/AIDS.

scholarly journals Prodrugs of NSAIDs: A Review

2017 ◽  
Vol 11 (1) ◽  
pp. 146-195 ◽  
Author(s):  
Kamal Shah ◽  
Jeetendra K. Gupta ◽  
Nagendra S. Chauhan ◽  
Neeraj Upmanyu ◽  
Sushant K. Shrivastava ◽  
...  
Keyword(s):  
Active Drug ◽  
Pharmacological Action ◽  
Patient Acceptance ◽  
Synergistic Activity ◽  
Bioavailability Enhancement ◽  
Drug Molecules ◽  
Presystemic Metabolism ◽  
Pass Through ◽  
Reduced Toxicity ◽  
Mutual Prodrug

Intoroduction:Prodrug approach deals with chemical biotransformation or enzymatic conversion or involves inactive or less active bio-reversible derivatives of active drug molecules. They have to pass through enzymatic or chemical biotransformation before eliciting their pharmacological action.Methods & Materials:The two different pharmacophores combine to give synergistic activity or may help in targeting the active drug to its target. Prodrug super seeds the problems of prodrug designing, for example solubility enhancement, bioavailability enhancement, chemical stability improvement, presystemic metabolism, site specific delivery, toxicity masking, improving patient acceptance, or eradicating undesirable adverse effects.Results:As an outcome the search for a prodrug or mutual prodrug with reduced toxicity has continued during recent years. This present review emphasizes the common help to revamp physiochemical, pharmaceutical and therapeutic effectiveness of drugs.Conclusion:This gives the researcher a common platform where they can find prodrugs of commonly used NSAIDs to overcome the gastrointestinal toxicity (irritation, ulcergenocity and bleeding).

scholarly journals Intranasal Delivery of Nanoformulations: A Potential Way of Treatment for Neurological Disorders

Molecules ◽  
2020 ◽  
Vol 25 (8) ◽  
pp. 1929 ◽  
Author(s):  
Salman Ul Islam ◽  
Adeeb Shehzad ◽  
Muhammad Bilal Ahmed ◽  
Young Sup Lee
Keyword(s):  
Drug Delivery ◽  
Neurological Disorders ◽  
Neurological Diseases ◽  
Nasal Delivery ◽  
Intranasal Route ◽  
Drug Molecules ◽  
Surface Enhanced ◽  
Effective Delivery ◽  
The Central Nervous System ◽  
The Brain

Although the global prevalence of neurological disorders such as Parkinson’s disease, Alzheimer’s disease, glioblastoma, epilepsy, and multiple sclerosis is steadily increasing, effective delivery of drug molecules in therapeutic quantities to the central nervous system (CNS) is still lacking. The blood brain barrier (BBB) is the major obstacle for the entry of drugs into the brain, as it comprises a tight layer of endothelial cells surrounded by astrocyte foot processes that limit drugs’ entry. In recent times, intranasal drug delivery has emerged as a reliable method to bypass the BBB and treat neurological diseases. The intranasal route for drug delivery to the brain with both solution and particulate formulations has been demonstrated repeatedly in preclinical models, including in human trials. The key features determining the efficacy of drug delivery via the intranasal route include delivery to the olfactory area of the nares, a longer retention time at the nasal mucosal surface, enhanced penetration of the drugs through the nasal epithelia, and reduced drug metabolism in the nasal cavity. This review describes important neurological disorders, challenges in drug delivery to the disordered CNS, and new nasal delivery techniques designed to overcome these challenges and facilitate more efficient and targeted drug delivery. The potential for treatment possibilities with intranasal transfer of drugs will increase with the development of more effective formulations and delivery devices.

scholarly journals Evolution of Mycolic Acid Biosynthesis Genes and Their Regulation during Starvation in Mycobacterium tuberculosis

2015 ◽  
Vol 197 (24) ◽  
pp. 3797-3811 ◽  
Author(s):  
Stevie Jamet ◽  
Yves Quentin ◽  
Coralie Coudray ◽  
Pauline Texier ◽  
Françoise Laval ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Outer Membrane ◽  
Cell Envelope ◽  
Stringent Response ◽  
Mycolic Acid ◽  
Content Type ◽  
New Targets ◽  
Key Enzyme ◽  
Unique Cell ◽  
Translational Apparatus

ABSTRACTMycobacterium tuberculosis, the etiological agent of tuberculosis, is a Gram-positive bacterium with a unique cell envelope composed of an essential outer membrane. Mycolic acids, which are very-long-chain (up to C100) fatty acids, are the major components of this mycomembrane. The enzymatic pathways involved in the biosynthesis and transport of mycolates are fairly well documented and are the targets of the major antituberculous drugs. In contrast, only fragmented information is available on the expression and regulation of the biosynthesis genes. In this study, we report that thehadA,hadB, andhadCgenes, which code for the mycolate biosynthesis dehydratase enzymes, are coexpressed with three genes that encode proteins of the translational apparatus. Consistent with the well-established control of the translation potential by nutrient availability, starvation leads to downregulation of thehadABCgenes along with most of the genes required for the synthesis, modification, and transport of mycolates. The downregulation of a subset of the biosynthesis genes is partially dependent on RelMtb, the key enzyme of the stringent response. We also report the phylogenetic evolution scenario that has shaped the current genetic organization, characterized by the coregulation of thehadABCoperon with genes of the translational apparatus and with genes required for the modification of the mycolates.IMPORTANCEMycobacterium tuberculosisinfects one-third of the human population worldwide, and despite the available therapeutic arsenal, it continues to kill millions of people each year. There is therefore an urgent need to identify new targets and develop a better understanding of how the bacterium is adapting itself to host defenses during infection. A prerequisite of this understanding is knowledge of how this adaptive skill has been implanted by evolution. Nutrient scarcity is an environmental condition the bacterium has to cope with during infection. In many bacteria, adaptation to starvation relies partly on the stringent response.M. tuberculosis's unique outer membrane layer, the mycomembrane, is crucial for its viability and virulence. Despite its being the target of the major antituberculosis drugs, only scattered information exists on how the genes required for biosynthesis of the mycomembrane are expressed and regulated during starvation. This work has addressed this issue as a step toward the identification of new targets in the fight againstM. tuberculosis.

scholarly journals The aceE involves in mycolic acid synthesis and biofilm formation in Mycobacterium smegmatis

2020 ◽  
Author(s):  
Suting Chen ◽  
Tianlu Teng ◽  
Shuan Wen ◽  
Tingting Zhang ◽  
Hairong Huang
Keyword(s):  
Cell Wall ◽  
Biofilm Formation ◽  
Morphological Changes ◽  
Acid Synthesis ◽  
Mycolic Acid ◽  
Colony Morphology ◽  
Wall Structure ◽  
Wild Type ◽  
Mycobacterial Cell Wall

Abstract Background: The integrity of cell wall structure is highly significant for the in vivo survival for mycobacteria. However, the mechanisms underlying the biosynthesis of mycobacterial cell wall remain poorly understood. aceE encodes the E1 component of pyruvate dehydrogenase (PDH)complex. This study aimed to know the functional role of aceE gene in cell wall biosynthesis in M. smegmatis.Results: We observed that the colony morphology of aceE-deficient mutants(aceE-mut)was quite different from the wild-type(WT) strain during the transposon library screening of M.smegmatis, smaller and smoother on the solid culture medium. Notably, the aceE-mut lost its ability of growing aggregately and biofilm forming, which are two very important features of mycobacteria.The morphological changes of the aceE-mut strain were further confirmed by electron microscopy that presented shorter, smoother and thinner images in contrast withWT strain.Additionally, the analysis of mycolic acid(MA)using LC-MS indicated deficiency of alpha-MA and epoxy-MA in aceE-mut strain whereas complementation of the aceE-mut with a wild-type aceEgene restored the composition of MA. Conclusions: Overall, this study indicates that aceE gene plays a significant role in the mycolic acid synthesis and affects the colony morphology and biofilm formation of M.smegmatis.

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