Identification of an Isoxazole Derivative as an Antitubercular Compound for Targeting the FadD Enzymes of .

FadD32, a fatty acyl-AMP ligase, plays an indispensable role in mycobacterial mycolic acid synthesis and is a validated target for tuberculosis (TB) drug development. The crystal structure of (Mtb)FadD32 has laid the foundation of structure-based drug discovery against this crucial enzyme. Here, we screened the "isoxazole" scaffold containing molecules against MtbFadD32 and identified a compound 2,4-dibromo-6-[3-(trifluoromethyl)-1,2-oxazol-5-yl]phenol (M1) with specific inhibitory activity against Mtb.

Mitigation of experimental ER stress and diabetes mellitus induced peripheral neuropathy by autophagy promoter, 6-BIO.

Neuropathy occurs due to damage to the peripheral/central nervous system either due to injury, disease, or drug usage. Increased endoplasmic reticulum (ER) stress is observed in neuropathy. ER stress also leads to a block in autophagy amplifying neuropathic pain.

Targeted suppression of MEP pathway genes DXS, IspD and IspF to explore the mycobacterial metabolism and survival.

Due to the uniqueness and essentiality of MEP pathway for the synthesis of crucial metabolites- isoprenoids, hopanoids, menaquinone etc. in mycobacterium, enzymes of this pathway are considered promising anti-tubercular drug targets. In the present study we seek to understand the consequences of downregulation of three of the essential genes- DXS, IspD, and IspF of MEP pathway using CRISPRi approach combined with transcriptomics in Mycobacterium smegmatis.

Antimycobacterial and healing effects of Pranlukast against MTB infection and pathogenesis in a preclinical mouse model of tuberculosis.

It is essential to understand the interactions and relationships between () and macrophages during the infection in order to design host-directed, immunomodulation-dependent therapeutics to control . We had reported previously that ornithine acetyltransferase (MtArgJ), a crucial enzyme of the arginine biosynthesis pathway of , is allosterically inhibited by pranlukast (PRK), which significantly reduces bacterial growth. The present investigation is centered on the immunomodulation in the host by PRK particularly the activation of the host's immune response to counteract bacterial survival and pathogenicity.

Multipronged regulation of autophagy and apoptosis: emerging role of TRIM proteins.

TRIM proteins are characterized by their conserved N-terminal RING, B-box, and coiled-coil domains. These proteins are efficient regulators of autophagy, apoptosis, and innate immune responses and confer immunity against viruses and bacteria. TRIMs function as receptors or scaffold proteins that target substrates for autophagy-mediated degradation.

CD44-SNA1 integrated cytopathology for delineation of high grade dysplastic and neoplastic oral lesions.

The high prevalence of oral potentially-malignant disorders exhibits diverse severity and risk of malignant transformation, which mandates a Point-of-Care diagnostic tool. Low patient compliance for biopsies underscores the need for minimally-invasive diagnosis. Oral cytology, an apt method, is not clinically applicable due to a lack of definitive diagnostic criteria and subjective interpretation.

Atomic visualization of flipped-back conformations of high mannose glycans interacting with cargo lectins: An MD simulation perspective.

Protein-carbohydrate interactions play a crucial role in mediating several biomolecular recognition events. We attempt to unravel its intricacies by understanding how carbohydrate-binding proteins interpret the glycan code. We aim to decipher lectin-mediated recognition in the endoplasmic reticulum (ER), which plays a crucial role in ER-mediated quality control (ER-QC).

Promotion of degradative autophagy by 6-bromoindirubin-3'-oxime attenuates neuropathy.

Damage to the central or peripheral nervous system causes neuropathic pain. Endoplasmic reticulum (ER) stress plays a role in peripheral neuropathy. Increase in ER stress is seen in diabetic neuropathy.

TLR4 activation by lysozyme induces pain without inflammation.

Mostly, pain has been studied in association with inflammation, until recent studies which indicate that during bacterial infections, pain mechanisms could be independent of the inflammation. Chronic pain can sustain long after the healing from the injury, even in the absence of any visible inflammation. However, the mechanism behind this is not known.

Structure and interactions of the phloem lectin (phloem protein 2) Cus17 from Cucumis sativus.

Phloem protein 2 (PP2) contributes crucially to phloem-based defense in plants by binding to carbohydrates displayed by pathogens. However, its three-dimensional structure and the sugar binding site remained unexplored. Here, we report the crystal structure of the dimeric PP2 Cus17 from Cucumis sativus in its apo form and complexed with nitrobenzene, N-acetyllactosamine, and chitotriose.

Mixed mechanism of conformational selection and induced fit as a molecular recognition process in the calreticulin family of proteins.

The fundamental question on the mechanism of molecular recognition during ligand binding has attracted a lot of scientific scrutiny. The two competing theories of ligand binding-"induced fit" and "conformational selection" have been proposed to explain biomolecular recognition. Since exploring a family of proteins with similar structural architectures and conserved functional roles can provide valuable insight into the significance of molecular structure and function, we performed molecular dynamics simulations on the calreticulin family of proteins, which specifically recognize monoglucosylated N-glycan during the protein folding process.

Rifampicin-Mediated Metabolic Changes in .

is considered to be a devastating pathogen worldwide, affecting millions of people globally. Several drugs targeting distinct pathways are utilized for the treatment of tuberculosis. Despite the monumental efforts being directed at the discovery of drugs for , the pathogen has also developed mechanisms to evade the drug action and host processes.

Metabolite Dysregulation by Pranlukast in .

has been infecting millions of people worldwide over the years, causing tuberculosis. Drugs targeting distinct cellular mechanisms including synthesis of the cell wall, lipids, proteins, and nucleic acids in are currently being used for the treatment of TB. Although extensive research is being carried out at the molecular level in the infected host and pathogen, the identification of suitable drug targets and drugs remains under explored.

Structure and Carbohydrate Recognition by the Nonmitogenic Lectin Horcolin.

Lectins are sugar-binding proteins that have shown considerable promise as antiviral agents because of their ability to interact with envelope glycoproteins present on the surface of viruses such as HIV-1. However, their therapeutic potential has been compromised by their mitogenicity that stimulates uncontrolled division of T-lymphocytes. Horcolin, a member of the jacalin family of lectins, tightly binds the HIV-1 envelope glycoprotein gp120 and neutralizes HIV-1 particles but is nonmitogenic.

Spike Protein and the Various Cell-Surface Carbohydrates: An Interaction Study.

The SARS-CoV-2 virus has been known to gain entry into the host cell through the spike protein that binds to the host ACE2 cell surface protein. However, the role of the putative sugar-binding sites in the spike protein has remained unclear. We provide a comprehensive outlook into the infection initiation wherein the virus first recognizes the sialosides on the cell via its S1A domain of the spike protein as it surfs over the cell surface.

C1 Inhibits Liquid-Liquid Phase Separation and Oligomerization of Tau and Protects Neuroblastoma Cells against Toxic Tau Oligomers.

The pathological aggregation of tau is one of the major contributing factors for several neurodegenerative tauopathies, including Alzheimer's disease. Here, we report that C1, a synthetic derivative of curcumin, strongly inhibited both the aggregation and filament formation of purified tau and protected neuroblastoma cells from the deleterious effects of the tau oligomers. Using confocal microscopy, C1 was found to reduce both the size and number of the tau droplets and increased the critical concentration of tau required for the droplet formation indicating that C1 suppressed the liquid-liquid phase separation of tau.

Mevo lectin specificity toward high-mannose structures with terminal αMan(1,2)αMan residues and its implication to inhibition of the entry of Mycobacterium tuberculosis into macrophages.

Mannose-binding lectins can specifically recognize and bind complex glycan structures on pathogens and have potential as antiviral and antibacterial agents. We previously reported the structure of a lectin from an archaeal species, Mevo lectin, which has specificity toward terminal α1,2 linked manno-oligosaccharides. Mycobacterium tuberculosis expresses mannosylated structures including lipoarabinomannan (ManLAM) on its surface and exploits C-type lectins to gain entry into the host cells.

Targeted nanoformulation of C1 inhibits the growth of KB spheroids and cancer stem cell-enriched MCF-7 mammospheres.

C1, a synthetic analog of curcumin, has been reported to show potent antiproliferative effects against a variety of cancer cells. Here, we report a strong anticancer activity of the folate receptor-targeted lipid nanoparticle formulation of C1 against cancer cells and cancer stem cells both in 2D culture and 3D spheroids. The size of the C1 encapsulated folic acid functionalized nanoliposomes (Lipos-C1) was determined to be 83 ± 17 nm.

Role of a cysteine residue in substrate entry and catalysis in MtHIBADH: Analysis by chemical modifications and site-directed mutagenesis.

Despite sharing conserved substrate-binding residues, members of 3-hydroxyisobutyrate dehydrogenase (HIBADH) superfamily show remarkable differences in substrate preference. Cysteine residues were identified within a radius of 6 Å surrounding both the active site and the substrate entry site of HIBADH enzyme from Mycobacterium tuberculosis (MtHIBADH). Chemical modification with thiol-modifying reagents, pCMB and DTNB, abrogated the dehydrogenase activity of the enzyme.

Targeting amino acid metabolism of Mycobacterium tuberculosis for developing inhibitors to curtail its survival.

Tuberculosis caused by the bacterium, Mycobacterium tuberculosis (Mtb), continues to remain one of the most devastating infectious diseases afflicting humans. Although there are several drugs for treating tuberculosis available currently, the emergence of the drug resistant forms of this pathogen has made its treatment and eradication a challenging task. While the replication machinery, protein synthesis and cell wall biogenesis of Mtb have been targeted often for anti-tubercular drug development a number of essential metabolic pathways crucial to its survival have received relatively less attention.