Abdur Rub

Host-lipidome as a potential target of protozoan parasites.

Host-lipidome caters parasite interaction by acting as first line of recognition, attachment on the cell surface, intracellular trafficking, and survival of the parasite inside the host cell. Here, we summarize how protozoan parasites exploit host-lipidome by suppressing, augmenting, engulfing, remodeling and metabolizing lipids to achieve successful parasitism inside the host.

Sphingosine-1-phosphate signaling: unraveling its role as a drug target against infectious diseases.

Sphingosine-1-phosphate (S1P) signaling is reported in variety of cell types, including immune, endothelial and cancerous cells. It is emerging as a crucial regulator of cellular processes, such as apoptosis, cell proliferation, migration, differentiation and so on. This signaling pathway is initiated by the intracellular production and secretion of S1P through a cascade of enzymatic reactions. Binding of S1P to different S1P receptors (S1PRs) activates different downstream signaling pathways that regulate the cellular functions differentially depending upon the cell type. An accumulating body of evidence suggests that S1P metabolism and signaling is often impaired during infectious diseases; thus, its manipulation might be helpful in the treatment of such diseases. In this review, we summarize recent advances in our understanding of the S1P signaling pathway and its candidature as a novel drug target against infectious diseases.

Orchestration of membrane receptor signaling by membrane lipids

Receptors on cell membrane bind to their respective ligands and transduce intracellular signals resulting in variety of effector functions. Membrane lipid composition determines the receptor signaling behavior, as the receptors assume different conformation to suit the biochemical milieu in its immediate vicinity in the membrane. Accordingly, these accommodate different signaling intermediates that dictate the course of intracellular signaling and the resulting effectors functions. In this review we provide an overview of how membrane lipids modulate membrane-properties, membrane-receptor functions and their significance in the host-pathogen interaction.

Proteome-wide B and T cell epitope repertoires in outer membrane proteins of Mycobacterium avium subsp. paratuberculosis have vaccine and diagnostic relevance: a holistic approach.

Mycobacterium avium subsp. paratuberculosis (MAP) is an etiological agent of chronic inflammation of the intestine among ruminants and humans. Currently, there are no effective vaccines and sensitive diagnostic tests available for its control and detection. For this, it is of paramount importance to identify the MAP antigens, which may be immunologically recognized by the host immune system. To address this challenge, we performed identification of the immunogenic epitopes in the MAP outer membrane proteins (OMPs). We have previously identified 57 MAP proteins as OMPs [Rana A, Rub A, Akhter Y. 2014. Molecular BioSystems, 10:2329–2337] and have evaluated them for the epitope selection and analysis employing a computational approach. Thirty‐five MAP OMPs are reported with nine‐mer peptides showing high binding affinity to major histocompatibility complex (MHC) class I molecules and 28 MAP OMPs with 15‐mer peptides of high binding affinity for MHC class II molecules. The presence of MHC binding epitopes indicates the potential cell‐mediated immune response inducing capacity of these MAP OMPs in infected host. To further investigate the humoral response inducing properties of OMPs of MAP, we report potential B cell epitopes based on the sequences of peptide antigens and their molecular structures. We also report 10 proteins having epitopes for both B and T cells representing potential candidates which may invoke both humoral and cellular immune responses in the host. These findings will greatly accelerate and expedite the formulation of effective and cost‐efficient vaccines and diagnostic tests against MAP infection. Copyright

A tug-of-war between the host and the pathogen generates strategic hotspots for the development of novel therapeutic interventions against infectious diseases

Microbial pathogens are known to express an array of specific signaling molecules referred as Pathogen Associated Molecular Patterns (PAMPs), which are recognized by Pattern Recognition Receptors (PRRs), present on the surface of the host cells. Interactions between PAMPs and PRRs on the surface of the host cells lead to signaling events which could culminate into either successful infection or clearance of the pathogens. Here, we summarize how these events may generate novel host based as well as pathogen based molecular targets for designing effective therapeutic strategies against infections.

Proteome-scale identification and characterization of mitochondria targeting proteins of Mycobacterium avium subspecies paratuberculosis: Potential virulence factors modulating host mitochondrial function

Mycobacterium avium subsp. paratuberculosis is the etiological agent of Johnes Disease among ruminants. During the course of infection, it expresses a number of proteins for its successful persistence inside the host that cause variety of physiological abnormalities in the host. Mitochondrion is one of the attractive targets for pathogenic bacteria. Employing a proteome-wide sequence and structural signature based approach we have identified 46 M. avium subsp. paratuberculosis proteins as potential targets for the host mitochondrial targeting. These may act as virulence factors modulating mitochondrial physiology for bacterial survival and immune evasion inside the host cells.

Screening of Novel Inhibitors Against Leishmania donovani Calcium ion Channel to Fight Leishmaniasis

Leishmania is an intracellular protozoan parasite which causes Leishmaniasis, a global health problem affecting millions of people throughout 89 different countries in the world. The current treatment which includes use of amphotericin B, antimonials, and others has major drawbacks due to toxicity, resistance, and extraordinary high cost. So there is an urgent need of development of new drug targets to fight against leishmaniasis. In this regard we have selected Leishmania donovani Ca2+ ion channel (Ld-CC) as potential drug target. Ld-CC regulates concentration of Ca2+ ions which is involved in several functions like flagellar motion, mitochondrial oxidative metabolism and entry inside the macrophages. Since Ld-CC has not been characterised yet, we performed homology modelling of Leishmania donovani Ca2+ ion channel (Ld-CC) and docking studies of ligand library against this channel. 542 compound library of National Cancer Institute (NCI) diversity 3 dataset selected for screening studies. The ligands ZINC17287336 and ZINC29590262 were selected as best energy conformers because they show highest binding affinity towards its target (Ld-CC). They interact with the active site residues in the pocket of Ld-CC which suggests that the docked conformations are good and acceptable. Moreover, these two selected compounds also have relatively high binding affinity than nifedipine and verapamil, known human calcium channel blockers which had been reported to have mild anti-leishmanial activity. Among these two top screened inhibitors the ligand ZINC29590262 shows poor binding affinity towards the Human voltagedependent L-type calcium channel subunit alpha-1C in comparison to the Ld-CC. Therefore, we proposed this ligand as the best inhibitor which shows 40% more binding affinity with Ld-CC than the human-VDCC. These results suggest that our screened ligand ZINC29590262 could act as novel drug and may show much better antileishmanial activity.

Identification of novel inhibitors against UDP-galactopyranose mutase to combat leishmaniasis†

Leishmania, a protozoan parasite that causes leishmaniasis, affects 1‐2 million people every year worldwide. Leishmaniasis is a vector born disease and characterized by a diverse group of clinical syndromes. Current treatment is limited because of drug resistance, high cost, poor safety, and low efficacy. The urgent need for potent agents against Leishmania has led to significant advances in the development of novel antileishmanial drugs. β‐galactofuranose (β‐Galf) is an important component of Leishmanial cell surface matrix and plays a critical role in the pathogenesis of parasite. UDP‐galactopyranose mutase (UGM) converts UDP‐galactopyranose (UDP‐Galp) to UDP‐galactofuranose (UDP‐Galf) which acts as the precursor for β‐Galf synthesis. Due to its absence in human, this enzyme is selected as the potential target in search of new antileishmanial drugs. Three dimensional protein structure model of Leishmania major UGM (LmUGM) has been homology modeled using Trypanosoma cruzi UGM (TcUGM) as a template. The stereochemistry was validated further. We selected already reported active compounds from PubChem database to target the LmUGM. Three compounds (6064500, 44570814, and 6158954) among the top hit occupied the UDP binding site of UGM suggested to work as a possible inhibitor for it. In vitro antileishmanial activity assay was performed with the top ranked inhibitor, 6064500. The 6064500 molecule has inhibited the growth of Leishmania donovani promastigotes significantly. Further, at similar concentrations it has exhibited significantly lesser toxicity than standard drug miltefosine hydrate in mammalian cells.

Implication of sphingosine-1-phosphate signaling in diseases: molecular mechanism and therapeutic strategies

Abstract Sphingosine-1-phosphate signaling is emerging as a critical regulator of cellular processes that is initiated by the intracellular production of bioactive lipid molecule, sphingosine-1-phosphate. Binding of sphingosine-1-phosphate to its extracellular receptors activates diverse downstream signaling that play a critical role in governing physiological processes. Increasing evidence suggests that this signaling pathway often gets impaired during pathophysiological and diseased conditions and hence manipulation of this signaling pathway may be beneficial in providing treatment. In this review, we summarized the recent findings of S1P signaling pathway and the versatile role of the participating candidates in context with several disease conditions. Finally, we discussed its possible role as a novel drug target in different diseases.

Anti-leishmanial and cytotoxic activities of amino acid-triazole hybrids: Synthesis, biological evaluation, molecular docking and in silico physico-chemical properties

According to WHO, leishmaniasis is a major tropical disease, ranking second after malaria. Significant efforts have been therefore invested into finding potent inhibitors for the treatment. In this work, eighteen novel 1,2,3-triazoles appended with l-amino acid (Phe/Pro/Trp) tail were synthesized via azide-alkyne click chemistry with moderate to good yield, and evaluated for their anti-leishmanial activity against promastigote form of Leishmania donovani (Dd8 strain). Among all, compounds 40, 43, and 53 were identified with promising anti-leishmanial activity with IC50=88.83±2.93, 96.88±12.88 and 94.45±6.51μM respectively and displayed no cytotoxicity towards macrophage cells. Moreover, compound 43 showed highest selectivity index (SI=8.05) among all the tested compounds. Supported by docking studies, the lead inhibitors (40, 43 and 53) showed interactions with key residues in the catalytic site of trypanothione reductase. The results of pharmacokinetic parameters suggest that these selected inhibitors can be carried forward for further structural optimization and pharmacological investigation.