Molecular, structural, and functional characterization of delta subunit of T-complex protein-1 from .

Chaperonins/Heat shock protein 60 are ubiquitous multimeric protein complexes that assist in the folding of partially and/or misfolded proteins using metabolic energy into their native stage. The eukaryotic group II chaperonin, also referred as T-complex protein-1 ring complex (TRiC)/T-complex protein-1 (TCP1)/chaperonin containing T-complex protein (CCT), contains 8-9 paralogous subunits, arranged in each of the two rings of hetero-oligomeric complex. In , till date, only one subunit, LdTCP1γ, has been well studied.

Epsilon subunit of T-complex protein-1 from Leishmania donovani: A tetrameric chaperonin.

The cytosolic T-complex protein-1 ring complex (TRiC), also referred as chaperonin containing TCP-1(CCT), comprising eight different subunits stacked in double toroidal rings, binds to around 10 % of newly synthesized polypeptides and facilitates their folding in ATP dependent manner. In Leishmania, among five subunits of TCP1 complex, identified either by transcriptome or by proteome analysis, only LdTCP1γ has been well characterized. It forms biologically active homo-oligomeric complex and plays role in protein folding and parasite survival.

Design, synthesis, and biological evaluation of quinoline-piperazine/pyrrolidine derivatives as possible antileishmanial agents.

In pursuance of our efforts to expand the scope of novel antileishmanial entities, a series of thirty-five quinoline-piperazine/pyrrolidine, and other heterocyclic amine derivatives were synthesized via a molecular hybridization approach and examined against intracellular amastigotes of luciferase-expressing Leishmania donovani. The preliminary in vitro screening suggests that twelve compounds in the series exhibited better inhibition against amastigote form with good IC values ranging from 2.09 to 8.

Antileishmanial evaluation of triazole-butenolide conjugates: design, synthesis, screening, SAR and ADME predictions.

In the quest to discover novel scaffolds with leishmanicidal effects, a series of 23 compounds containing the most promising 1,2,3-triazole and highly potent butenolide in one framework were synthesized. The synthesized conjugates were screened against parasite; five of them showed moderate antileishmanial activity against promastigotes (IC 30.6 to 35.

Design and synthesis of N-acyl and dimeric N-Arylpiperazine derivatives as potential antileishmanial agents.

The current regime for leishmaniasis is associated with several adverse effects, expensive, parenteral treatment for longer periods and the emergence of drug resistance. To develop affordable and potent antileishmanial agents, a series of N-acyl and homodimeric aryl piperazines were synthesized with high purity, predicted druggable properties by in silico methods and investigated their antileishmanial activity. The in vitro biological activity of synthesized compounds against clinically validated intracellular amastigote and extracellular promastigote form of Leishmania donovani parasite showed eight compounds inhibited 50% amastigotes growth below 25 µM.

Design and synthesis of novel halogen rich salicylanilides as potential antileishmanial agents.

The available therapeutic treatment for leishmaniasis is inadequate and toxic due to side effects, expensive and emergence of drug resistance. Affordable and safe antileishmanial agents are urgently needed and toward this objective, we synthesized a series of 32 novel halogen rich salicylanilides including niclosamide and oxyclozanide and investigated their antileishmanial activity against amastigotes of Leishmania donovani. In vitro data showed fifteen compounds inhibited intracellular amastigotes with an IC of below 5 μM and selectivity index above 10.

Dipeptidylcarboxypeptidase Inhibitor as a Potential Oral Treatment for Visceral Leishmaniasis.

Chemotherapy is the key intervention to control visceral leishmaniasis (VL), a neglected tropical disease. Current regimens include not only a few drugs but also present several drawbacks, including moderate to severe toxicity, cost, long-term administration, patient compliance, and growing drug resistance. Thus, the need for better treatment options against VL is a priority.

Downregulation of gamma subunit of TCP1 chaperonin of Leishmania donovani modulates extracellular vesicles-mediated macrophage microbicidal function.

T-complex protein-1 (TCP1) is a group II chaperonin, known to fold various proteins like actin and tubulin. In Leishmania donovani only one subunit that is gamma subunit (LdTCP1γ) has been functionally characterized as a homo-oligomeric complex that exhibits ATP-dependent protein folding. The gene is essential for the survival and infectivity of the parasite.

Dipeptidylcarboxypeptidase of Leishmania donovani: A potential vaccine molecule against experimental visceral leishmaniasis.

Visceral leishmaniasis is one of the deadliest parasitic diseases in the world. In the absence of an efficient and cost-effective drugs, development of an effective vaccine is the need of the day. In spite of several efforts, a successful vaccine against the disease has been elusive.

Unraveling of interacting protein network of chaperonin TCP1 gamma subunit of Leishmania donovani.

T-complex polypeptide-1 (TCP1) is a group II chaperonin that folds various cellular proteins. About 10% of cytosolic proteins in yeast have been shown to flux through the TCP1 protein complex indicating that it interacts and folds a plethora of substrate proteins that perform essential functions. In Leishmania donovani, the gamma subunit of TCP1 (LdTCP1γ) has been shown to form a homo-oligomeric complex and exhibited ATP-dependent protein folding activity.

Immunological characterization of rLdTCP1γ for its prophylactic potential against visceral leishmaniasis in hamster model.

Visceral leishmaniasis (VL) is a chronic tropical disease responsible for devastating epidemics worldwide. Though current treatment relies on drugs, the emergence of resistance, toxic side-effects, and strenuous administration has led to an ineffective remedy. Hence, vaccination remains an alternative and desirable approach for VL control.

Pathogenic role of mitogen activated protein kinases in protozoan parasites.

Protozoan parasites with complex life cycles have high mortality rates affecting billions of human lives. Available anti-parasitic drugs are inadequate due to variable efficacy, toxicity, poor patient compliance and drug-resistance. Hence, there is an urgent need for the development of safer and better chemotherapeutics.

Comparative phosphoproteomic analysis unravels MAPK1 regulated phosphoproteins in Leishmania donovani.

Mitogen Activated Protein Kinase1 (MAPK1) of Leishmania donovani functions as key regulators of various cellular activities, which seem to be imperative for parasite survival, infectivity, drug resistance and post-translational modification of chaperones/co-chaperones. However, very less is known about LdMAPK1 target proteins. With recent advancements in proteomics, we aimed to identify phosphoproteins which were differentially expressed in LdMAPK1 overexpressing (Dd8++/++) and single replacement mutants (Dd8+/) as compared to wild type (Dd8+/+) parasites, utilizing LC-MS/MS approach.

Leishmania donovani chaperonin TCP1γ subunit protects miltefosine induced oxidative damage.

T-complex protein-1 (TCP1) is a chaperonin protein known to fold various proteins like actin and tubulin. In Leishmania donovani only one subunit of TCP1 that is gamma subunit (LdTCP1γ) has been functionally characterized. It not only performs ATP dependent protein folding but is also essential for survival and virulence.

Antileishmanial assessment of isoxazole derivatives against .

A chemical library comprising substituted 3-nitroisoxazoles and 3-aminoisoxazoles was prepared and screened for their antileishmanial activity against . As compared to Miltefosine, the standard drug used in bioassays, several compounds displayed remarkably better inhibition of the promastigote and amastigote stages of parasites. The evaluation of a few compounds in a golden hamster model showed significant reduction of the parasite load post treatment the intraperitoneal route by several compounds.

Estrogens as regulator of hematopoietic stem cell, immune cells and bone biology.

Hematopoietic stem cells provide continuous supply of all the immune cells, through proliferation and differentiation decisions. These decisions are controlled by local bone marrow environment as well as by long-range signals for example endocrine system. Sex dependent differential immunological responses have been described under homeostasis and disease conditions.

Guanylate Binding Proteins Restrict Leishmania donovani Growth in Nonphagocytic Cells Independent of Parasitophorous Vacuolar Targeting.

Interferon (IFN)-inducible guanylate binding proteins (GBPs) play important roles in host defense against many intracellular pathogens that reside within pathogen-containing vacuoles (PVs). For instance, members of the GBP family translocate to PVs occupied by the protozoan pathogen and facilitate PV disruption and lytic parasite killing. While the GBP defense program targeting has been studied in some detail, the role of GBPs in host defense to other protozoan pathogens is poorly characterized.

TCP1γ Subunit Is Indispensable for Growth and Infectivity of Leishmania donovani.

T-complex protein-1 (TCP1) is a ubiquitous group II chaperonin and is known to fold various proteins, such as actin and tubulin. In , the γ subunit of TCP1 (LdTCP1γ) has been cloned and characterized. It forms a high-molecular-weight homo-oligomeric complex that performs ATP-dependent protein folding.

Efficient antileishmanial activity of amphotericin B and piperine entrapped in enteric coated guar gum nanoparticles.

Amphotericin B (AmB) exhibits potential antileishmanial activity, with only a little rate of recurrence. However, low bioavailability and severe nephrotoxicity are among the major shortcomings of AmB-based therapy. Various AmB nanoformulations have been developed, which to an extent, have reduced its toxicity and increased the drug efficacy.

Identification of potential anti-leishmanial agents using computational investigation and biological evaluation against trypanothione reductase.

Trypanothione reductase of is a flavin adenine dinucleotide containing homodimeric protein essential for parasite survival. The flavoenzyme utilizes nicotinamide adenine dinucleotide phosphate in the reaction to convert oxidized trypanothione to reduced trypanothione which is further used up by tryparedoxin/tryparedoxin peroxidase system to neutralize the reactive oxygen species generated by the macrophages. Some of the drugs previously reported against the disease include sodium stibogluconate, miltefosine and amphotericin B.

An insight into tetrahydro-β-carboline-tetrazole hybrids: synthesis and bioevaluation as potent antileishmanial agents.

A series of 2,3,4,9-tetrahydro-β-carboline tetrazole derivatives () have been synthesized utilizing the Ugi multicomponent reaction and were identified as potential antileishmanial chemotypes. Most of the screened derivatives exhibited significant activity against the promastigote (IC from 0.59 ± 0.

Synthesis and evaluation of novel triazolyl quinoline derivatives as potential antileishmanial agents.

The high potential of quinoline containing natural products and their derivatives in medicinal chemistry led us to discover novel series of 25 compounds for the development of new antileishmanial agents. A series of triazolyl 2-methyl-4-phenylquinoline-3-carboxylate derivatives has been synthesized via click chemistry inspired molecular hybridization approach and evaluated against Leishmania donovani. Most of the screened derivatives exhibited significant in vitro anti-leishmanial activity against promastigote (IC ranging from 2.

MAPK1 of Leishmania donovani interacts and phosphorylates HSP70 and HSP90 subunits of foldosome complex.

MAP kinases (MAPK) are the most downstream kinases in signal transduction cascades and regulate critical cellular activities such as cell proliferation, differentiation, mortality, stress response, and apoptosis. The Leishmania donovani MAPK1 (LdMAPK1) is involved in parasite viability and drug resistance, but its substrates have not been identified yet. Aiming to identify the possible targets(s) of LdMAPK1, we sought to isolate interacting partners by co-immunoprecipitation, gel electrophoresis and mass spectrometry.

Nanotized Curcumin and Miltefosine, a Potential Combination for Treatment of Experimental Visceral Leishmaniasis.

Leishmaniasis chemotherapy remains very challenging due to high cost of the drug and its associated toxicity and drug resistance, which develops over a period of time. Combination therapies (CT) are now in use to treat many diseases, such as cancer and malaria, since it is more effective and affordable than monotherapy. CT are believed to represent a new explorable strategy for leishmaniasis, a neglected tropical disease caused by the obligate intracellular parasite In the present study, we investigated the effect of a combination of a traditional Indian medicine (ayurveda), a natural product curcumin and miltefosine, the only oral drug for visceral leishmaniasis (VL) using a -hamster model.