Hemanta K Majumder

Indian Institute of Chemical Biology, Kolkata, West Bengal, India

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Publications (104)368.69 Total impact

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    ABSTRACT: Chemical investigation of the stem of Thalictrum foliolosum resulted in the isolation of two new bisbenzylisoquinoline alkaloids (1 and 2) along with known protoberberine group of isoquinoline alkaloids thalifendine (3) and berberine (4). The structures of the new compounds were established by detailed 2D NMR spectral analysis with their configurations determined from their optical rotation values and confirmed using circular dichroism. Inhibitory activities of these four compounds against DNA topoisomerase IB of Leishmania donovani were evaluated. Compound 2 exhibited almost complete inhibition of the enzyme activity at 50μM concentration and it was found to be effective in killing both wild type as well as SAG resistant promastigotes of the parasite.
    No preview · Article · Nov 2015 · Fitoterapia
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    Full-text · Dataset · Aug 2015
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    ABSTRACT: DNA topoisomerase II inhibitors e.g. doxorubicin and etoposide are currently used in the chemotherapy for acute lymphoblastic leukemia (ALL). These inhibitors have serious side effects during the chemotherapy e.g. cardiotoxicity and secondary malignancies. In this study we show that sulfonoquinovosyl diacylglyceride (SQDG) isolated from Azadirachta indica exerts potent anti-ALL activity both in vitro and in vivo in nude mice and it synergizes with doxorubicin and etoposide. SQDG selectively targets ALL MOLT-4 cells by inhibiting catalytic activity of topoisomerase I enzyme and inducing p53 dependent apoptotic pathway. SQDG treatment induces recruitment of ATR at chromatin and arrests the cells in S-phase. Down-regulation of topoisomerase I or p53 renders the cells less sensitive for SQDG, while ectopic expression of wild type p53 protein in p53 deficient K562 cells results in chemosensitization of the cells for SQDG. We also show that constant ratio combinations of SQDG and etoposide or SDQG and doxorubicin exert synergistic effects on MOLT-4 cell killing. This study suggests that doses of etoposide/doxorubicin can be substantially reduced by combining SQDG with these agents during ALL chemotherapy and side effects caused can be minimized. Thus dual targeting of topoisomerase I and II enzymes is a promising strategy for improving ALL chemotherapy.
    Full-text · Article · Jul 2015 · Scientific Reports
  • Chetan Kumar Jain · Susanta Roychoudhury · Hemanta Kumar Majumder
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    ABSTRACT: Cancer cells with defective DNA decatenation checkpoint can be selectively targeted by the catalytic inhibitors of DNA topoisomerase IIα (topo IIα) enzyme. Upon treatment with catalytic topo IIα inhibitors, cells with defective decatenation checkpoint fail to arrest their cell cycle in G2 phase and enter into M phase with catenated and under-condensed chromosomes resulting into impaired mitosis and eventually cell death. In the present work we analyzed decatenation checkpoint in five different colon cancer cell lines (HCT116, HT-29, Caco2, COLO 205 and SW480) and in one non-cancerous cell line (HEK293T). Four out of the five colon cancer cell lines i.e. HCT116, HT-29, Caco2, and COLO 205 were found to be compromised for the decatenation checkpoint function at different extents, whereas SW480 and HEK293T cell lines were found to be proficient for the checkpoint function. Upon treatment with ICRF193, decatenation checkpoint defective cell lines failed to arrest the cell cycle in G2 phase and entered into M phase without proper chromosomal decatenation, resulting into the formation of tangled mass of catenated and under-condensed chromosomes. Such cells underwent mitotic catastrophe and rapid apoptosis like cell death and showed higher sensitivity for ICRF193. Our study suggests that catalytic inhibitors of topoisomerase IIα are promising therapeutic agents for the treatment of colon cancers with defective DNA decatenation checkpoint. Copyright © 2015. Published by Elsevier B.V.
    No preview · Article · Mar 2015 · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
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    ABSTRACT: Dispiro andrographolide derivatives have been prepared from isatin/acenaphthoquinone, N-benzyl glycine and andrographolide via azomethine ylide cycloaddition reaction. The cytotoxic effect of the synthesized molecules has been studied against MCF-7 breast cancer cell line. The compounds induced apoptotic cell death as revealed by increased labeling with Annexin-V, decreased polarization of cell mitochondria, and increased reactive oxygen species production. Using FACS and western blot analysis, the compounds were observed to block the cell cycle at S phase. Activation of caspases 7 and 9 suggested that caspase pathways were involved in inducing apoptosis.
    Full-text · Article · Jan 2015 · Medicinal Chemistry Communication
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    ABSTRACT: Leishmania, a protozoan parasite, causes a wide range of human diseases ranging from the localized self-healing cutaneous lesions to fatal visceral leishmaniasis. Toxicity of traditional first line drugs and emergence of drug-resistant strains have worsened the situation. DNA topoisomerase II in kinetoplastid protozoan parasites are of immense interest as drug target because they take part in replication of unusual kinetoplast DNA network. In this study, we have taken target-based therapeutic approaches to combat leishmaniasis. Two isobenzofuranone compounds, viz., (1) 3,5-bis(4-chlorophenyl)-7-hydroxyisobenzofuran-1(3H)-one (JVPH3) and (2) (4-bromo)-3′-hydroxy-5′-(4-bromophenyl)-benzophenone(JVPH4) were synthesized chemically and characterized by NMR and mass spectrometry analysis. Activity of type II DNA topoisomerase of leishmania (LdTOPII) was monitored by decatenation assay and plasmid cleavage assay. The antiparasitic activity of these compounds was checked in experimental BALB/c mice model of visceral leishmaniasis. Isobenzofuranone derivatives exhibited potent antileishmanial effect on both antimony (Sb) sensitive and resistant parasites. Treatment with isobenzofuranone derivatives on promastigotes caused induction of reactive oxygen species (ROS)-mediated apoptosis like cell death in leishmania. Both the compounds inhibited the decatenation activity of LdTOPII but have no effect on bi-subunit topoisomerase IB. Treatment of LdTOPII with isobenzofuranone derivatives did not stabilize cleavage complex formation both in vitro and in vivo. Moreover, treatment with isobenzofuranone derivatives on Leishmania donovani-infected mice resulted in clearance of parasites in liver and spleen by induction of Th1 cytokines. Taken together, our data suggest that these compounds can be exploited as potential antileishmanial agents targeted to DNA topoisomerase II of the parasite.
    Full-text · Article · Dec 2014
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    ABSTRACT: Chemical investigation of the stem bark of Anthocephalus cadamba has resulted in the isolation of anthocephaline (1), a new indole alkaloid, along with strictosamide (2), vincosamide (3) and cadambine (4). The structures of the isolated alkaloids (1-4) were established by detailed 2D NMR spectral analysis. Cadambine (4) exhibited potent DNA topoisomerase IB inhibitory activity.
    No preview · Article · Nov 2014 · Natural product communications
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    ABSTRACT: Hydroxy-9,10-anthraquinones are present at the core of anthracycline anticancer drugs. Reactive oxygen species (ROS) formed by anthracyclines increase anti-tumor activity but are cardiotoxic. Metal-anthracyclines generate relatively less ROS but are effective antitumor agents. Purpurin (LH3), a hydroxy-9,10-anthraquinone, closely resembles the established anthracycline doxorubicin. It was chosen for this work to see the extent to which a simpler analogue was effective. A Cu(II) complex of LH3 [Cu(II)-(LH2)2] was synthesized to mimic the metal-anthracycline complexes. The structure obtained for [Cu(II)-(LH2)2] is the first crystal structure of any hydroxy-9,10-anthraquinone with a 3d-transition metal ion solved from powder X-ray diffraction data and corroborated by DFT calculations. DNA binding of the complex was slightly better than purpurin but more importantly unlike purpurin, binding constant values did not decrease with increase in the pH of the medium. DNA relaxation assays show Cu(II)-(LH2)2 as a novel potent dual inhibitor of human DNA topoisomerase I and human DNA topoisomerase II enzymes. Cu(II)-(LH2)2 stabilizes covalent topoisomerase-DNA complexes both in-vitro and within cancer cells. Cleavage assays keep the complex well ahead of LH3 with regard to efficacy. These results paralleled those of cell growth inhibition and showed that the complex was more effective in killing ALL MOLT-4 cells than LH3, suggesting the complex targets topoisomerase enzymes within cells. The NADH dehydrogenase assay showed generation of superoxide was less for the complex compared to LH3 that helps to explain why the complex could be less cardiotoxic if tried as an anticancer agent.
    Full-text · Article · Oct 2014 · RSC Advances
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    ABSTRACT: In parasites, ATP binding cassette (ABC) transporters represent an important family of proteins related to drug resistance and other biological activities. Resistance of leishmanial parasites to therapeutic drugs continues to escalate in developing countries and in many instances it is due to overexpressed ABC efflux pumps. Progressively adapted baicalein (BLN)resistant parasites (pB25R) show overexpression of a novel ABC transporter, which was classified as ABCC2 or LdMrp2. The protein is primarily localized in the flagellar pocket region and in internal vesicles. Overexpressed LdABCC2 confers substantial BLN resistance to the parasites by rapid drug efflux. The BLN-resistant promastigotes when transformed into amastigotes in macrophage cells cannot be cured by treatment of macrophages with BLN. Amastigotes resistance is concomitant to the over expression of macrophage multidrug resistance protein 2 (MRP2) transporter. Reporter analysis and site directed mutagenesis assays demonstrate that antioxidant response element (ARE) 1 is activated upon infection. The expression of this phase II detoxifying gene is regulated by Nrf2 (NFE2 related factor 2) mediated antioxidant response element (ARE) activation. In view of the fact that the signaling pathway of phospho inositol 3 kinase controls microfilament rearrangement and translocation of actin associated proteins, the current study correlates with intricate pathway of PI3 kinase mediated nuclear translocation of Nrf2 which activates Mrp2 expression in macrophages upon infection by the parasites. In contrast, phalloidin, an agent that prevents actin filaments from depolymerization, inhibits Nrf2 translocation and Mrp2 activation by pB25R infection. Taken together, these results provide an insight into the mechanisms by which resistant clinical isolates of Leishmania donovani induce intracellular events relevant to drug resistance.
    Preview · Article · Apr 2014 · Journal of Biological Chemistry
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    ABSTRACT: Poly(ADP-ribose) polymerases (PARP) attach poly(ADP-ribose) (PAR) chains to various proteins including themselves and chromatin. Topoisomerase I (Top1) regulates DNA supercoiling and is the target of camptothecin and indenoisoquinoline anticancer drugs, as it forms Top1 cleavage complexes (Top1cc) that are trapped by the drugs. Endogenous and carcinogenic DNA lesions can also trap Top1cc. Tyrosyl-DNA phosphodiesterase 1 (TDP1), a key repair enzyme for trapped Top1cc, hydrolyzes the phosphodiester bond between the DNA 3'-end and the Top1 tyrosyl moiety. Alternative repair pathways for Top1cc involve endonuclease cleavage. However, it is unknown what determines the choice between TDP1 and the endonuclease repair pathways. Here we show that PARP1 plays a critical role in this process. By generating TDP1 and PARP1 double-knockout lymphoma chicken DT40 cells, we demonstrate that TDP1 and PARP1 are epistatic for the repair of Top1cc. The N-terminal domain of TDP1 directly binds the C-terminal domain of PARP1, and TDP1 is PARylated by PARP1. PARylation stabilizes TDP1 together with SUMOylation of TDP1. TDP1 PARylation enhances its recruitment to DNA damage sites without interfering with TDP1 catalytic activity. TDP1-PARP1 complexes, in turn recruit X-ray repair cross-complementing protein 1 (XRCC1). This work identifies PARP1 as a key component driving the repair of trapped Top1cc by TDP1.
    Full-text · Article · Feb 2014 · Nucleic Acids Research
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    ABSTRACT: The unicellular organism Leishmania undergoes apoptosis-like cell death in response to external stress or exposure to antileishmanial agents. Here, we showed that 3-O,28-O-disuccinyl betulin (DiSB), a potent topoisomerase type IB inhibitor, induced parasitic cell death by generating oxidative stress. The characteristic feature of the death process resembled the programmed cell death (PCD) seen in higher eukaryotes. In the current study, the generation of reactive oxygen species (ROS), followed by the depolarization of mitochondrial membrane potential (ΔΨm), caused a loss in ATP production in Leishmania parasites. This further gave positive feedback to produce a large amount of ROS, which in turn caused oxidative DNA lesions and genomic DNA fragmentation. The treatment of promastigotes with DiSB induced high expression levels of metacaspase protein that led to cell death in this unicellular organism. The PCD was insensitive to benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone (zVAD-fmk), suggesting that the death process was not associated with the activation of caspases. DiSB treatment translocated Leishmania donovani endonuclease G (LdEndoG) from mitochondria to the nucleus, which was responsible for the DNA degradation process. Conditional antisense knockdown of L. donovani metacaspase (LdMC), as well as EndoG, -subverted death of the parasite and rescued cell cycle arrest in G1 phase. The present study on the effector molecules associated with the PCD pathway of the parasite should help to manifest the mechanisms of PCD and also might be exploited in antileishmanial chemotherapy.
    No preview · Article · Jan 2014 · Antimicrobial Agents and Chemotherapy
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    ABSTRACT: Lignans are diphenyl propanoids with vast range of biological activities. The present study provides an important insight into the anti-leishmanial activities of two lignan glycosides viz. lyoniside and saracoside. These compounds inhibit catalytic activities of topoisomerase IB (LdTopIB) of Leishmania donovani in non-competitive manner and stabilize the LdTopIB mediated cleavage complex formation both in-vitro and in Leishmania promastigotes and subsequently inhibit the religation of cleaved strand. These two compounds not only poison LdTopIB but also can interact with the free enzyme LdTopIB. We have also shown that lyoniside and saracoside are cytotoxic to promastigotes and intracellular amastigotes. The protein-DNA complex formation leads to double strand breaks in DNA which ultimately triggers apoptosis-like cell death in the parasitie. Along with their cytotoxicity towards sodium antimony gluconate (SAG) sensitive AG83 strain, their ability to kill SAG resistant GE1 strain makes these two compounds potential anti-leishmanial candidates. Not only they effectively kill L. donovani amastigotes inside macrophages in vitro, lyoniside and saracoside demonstrated strong anti-leishmanial efficacies in BALB/c mice model of leishmaniasis. Treatment with these lignan glycosides produce nitric oxide and reactive oxygen species which result in almost complete clearance of the liver and splenic parasite burden. These compounds do not inhibit human topoisomerase IB upto 200μM concentrations and had poor cytotoxic effect on uninfected cultured murine peritoneal macrophages upto 100μM concentrations. Taken together it can be concluded that these compounds can be developed into excellent therapeutic agent against deadly disease leishmaniasis.
    No preview · Article · Oct 2013 · Biochemical pharmacology
  • Garima Sharma · Sayan Chowdhury · Suman Sinha · Hemanta K Majumder · S Vasanth Kumar
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    ABSTRACT: Abstract For the development of potent novel antileishmanial agents, 3,3'-(arylmethylene)bis(2-hydroxynaphthalene-1,4 dione) derivatives were synthesized from lawsone and evaluated for cytotoxicity on Leishmania donovani promastigotes as well as on leishmanial DNA topoisomerase-I. Enzyme inhibition studies were conducted with simultaneous and preincubation conditions. Total inhibition is compared to camptothecin (CPT), which was taken as positive control on both the systems of enzyme inhibition. The range of activity varied from 37.5 to 70 µM in simultaneous assay and 13-16 µM in preincubation assay. Furthermore, when evaluated against L. donovani promastigotes, the synthesized compounds exhibited the activity ranging from 2 to 14 µM. The results revealed that all the compounds exhibit promising antileishmanial activity.
    No preview · Article · Mar 2013 · Journal of Enzyme Inhibition and Medicinal Chemistry
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    ABSTRACT: Niranthin, a lignan isolated from the aerial parts of the plant Phyllanthus amarus, exhibits a wide spectrum of pharmacological activities. In the present study, we have shown for the first time that niranthin is a potent anti-leishmanial agent. The compound induces topoisomerase I-mediated DNA-protein adduct formation inside Leishmania cells and triggers apoptosis by activation of cellular nucleases. We also show that niranthin inhibits the relaxation activity of heterodimeric type IB topoisomerase of L. donovani and acts as a non-competitive inhibitor interacting with both subunits of the enzyme. Niranthin interacts with DNA-protein binary complexes and thus stabilizes the 'cleavable complex' formation and subsequently inhibits the religation of cleaved strand. The compound inhibits the proliferation of Leishmania amastigotes in infected cultured murine macrophages with limited cytotoxicity to the host cells and is effective against antimony-resistant Leishmania parasites by modulating upregulated P-glycoprotein on host macrophages. Importantly, besides its in vitro efficacy, niranthin treatment leads to a switch from a Th2- to a Th1-type immune response in infected BALB/c mice. The immune response causes production of nitric oxide, which results in almost complete clearance of the liver and splenic parasite burden after intraperitoneal or intramuscular administration of the drug. These findings can be exploited to develop niranthin as a new drug candidate against drug-resistant leishmaniasis.
    Full-text · Article · Oct 2012 · EMBO Molecular Medicine
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    ABSTRACT: Chemical investigation of the stem bark of Saraca indica has resulted in the isolation of a new lignan glycoside, saracoside, along with four known lignan glycosides lyoniside, icariside E3, (+)5'-methoxyisolarciresinol-9'-O-beta-D-glucopyranoside and nudiposide, and a phenolic glucopyranoside, 3,4,5-trimethoxyphenyl-beta-D-glucopyranoside, which has been isolated for the first time from this species. The isolated lignan glycosides exhibit potent DNA topoisomerase IB inhibitory activity.
    No preview · Article · Jun 2012 · Natural product communications
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    ABSTRACT: The development of 3, 3'-diindolyl methane (DIM) resistant parasite Leishmania donovani (LdDR50) by adaptation with increasing concentrations of the drug generates random mutations in the large and small subunits of heterodimeric DNA topoisomerase I of Leishmania (LdTOP1LS). Mutation of large subunit of LdTOP1LS at F270L is responsible for resistance to DIM up to 50 µM concentration. In search of compounds that inhibit the growth of the DIM resistant parasite and inhibit the catalytic activity of mutated topoisomerase I (F270L), we have prepared three derivatives of DIM namely DPDIM (2,2'-diphenyl 3,3'-diindolyl methane), DMDIM (2,2'-dimethyl 3,3'-diindolyl methane) and DMODIM (5,5'-dimethoxy 3,3'-diindolyl methane) from parent compound DIM. All the compounds inhibit the growth of DIM resistant parasites, induce DNA fragmentation and stabilize topo1-DNA cleavable complex with the wild type and mutant enzyme. The results suggest that the three derivatives of DIM can act as promising lead molecules for the generation of new anti-leishmanial agents.
    Full-text · Article · Dec 2011 · PLoS ONE
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    ABSTRACT: Toward developing antileishmanial agents with mode of action targeted to DNA topoisomerases of Leishmania donovani, we have synthesized a large number of derivatives of betulin. The compound, a natural triterpene isolated from the cork layer of Betula spp. plants exhibits several pharmacological properties. Three compounds (disuccinyl betulin, diglutaryl dihydrobetulin, and disuccinyl dihydrobetulin) inhibit growth of the parasite as well as relaxation activity of the enzyme type IB topoisomerase [Leishmania donovani topoisomerase I (LdTOP1LS)] of the parasite. Mechanistic studies suggest that these compounds interact with the enzyme in a reversible manner. The stoichiometry of these compounds binding to LdTOP1LS is 1:1 (mole/mole) with a dissociation constant on the order of ∼10(-6) M. Unlike CPT, these compounds do not stabilize the cleavage complex; rather, they abrogate the covalent complex formation. In processive mode of relaxation assay condition, these compounds slow down the strand rotation event, which ultimately affects the relaxation of supercoiled DNA. It is noteworthy that these compounds reduce the intracellular parasite burden in macrophages infected with wild-type L. donovani as well as with sodium antimony gluconate resistant parasite (GE1). Taken together, our data suggest that these betulin derivatives can be exploited as potential drug candidates against threatening drug resistant leishmaniasis.
    No preview · Article · Oct 2011 · Molecular Pharmacology
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    Hemanta K Majumder · Wanderley de Souza · Kwang Poo Chang

    Preview · Article · Aug 2011
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    ABSTRACT: Toward developing antileishmanial agents with mode of action targeted to DNA topoisomerases of Leishmania donovani, we have synthesized a large number of derivatives of betulin. The compound, a natural triterpene isolated from the cork layer of Betula spp. plants exhibits several pharmacological properties. Three compounds (disuccinyl betulin, diglutaryl dihydrobetulin, and disuccinyl dihydrobetulin) inhibit growth of the parasite as well as relaxation activity of the enzyme type IB topoisomerase [Leishmania donovani topoisomerase I (LdTOP1LS)] of the parasite. Mechanistic studies suggest that these compounds interact with the enzyme in a reversible manner. The stoichiometry of these compounds binding to LdTOP1LS is 1:1 (mole/mole) with a dissociation constant on the order of ∼10(-6) M. Unlike CPT, these compounds do not stabilize the cleavage complex; rather, they abrogate the covalent complex formation. In processive mode of relaxation assay condition, these compounds slow down the strand rotation event, which ultimately affects the relaxation of supercoiled DNA. It is noteworthy that these compounds reduce the intracellular parasite burden in macrophages infected with wild-type L. donovani as well as with sodium antimony gluconate resistant parasite (GE1). Taken together, our data suggest that these betulin derivatives can be exploited as potential drug candidates against threatening drug resistant leishmaniasis.
    No preview · Article · Jul 2011 · Molecular pharmacology
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    Bijoylaxmi Banerjee · Nilkantha Sen · Hemanta K Majumder
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    ABSTRACT: DNA topoisomerases of kinetoplastids represent a family of DNA processing enzymes that essentially solve the topological problems not only in nuclear DNA but also in kinetoplast DNA. We have, for the first time, identified a Leishmania donovani homologue of bacterial and eukaryotic IA type of topoisomerase III protein and termed as LdTopIIIβ. Complementation study of wild-type and mutant LdTopIIIβ with slow-growing topoisomerase III mutant yeast S. cerevisiae revealed the functional conservation of the leishmanial counterpart of topoisomerase IIIβ protein, the 327 tyrosine being the active site amino acid. A C-terminal deletion construct of LdTopIIIβ could not suppress the slow-growth phenotype of mutant yeast, indicating the requirement of C-terminal region for the enzyme function in vivo.LdTopIIIβ localized inside the nucleus and kinetoplast of the parasite. Taken together, our study indicates functional conservation and possible role of LdTopIIIβ in parasite DNA processing.
    Full-text · Article · May 2011

Publication Stats

2k Citations
368.69 Total Impact Points

Institutions

  • 1988-2015
    • Indian Institute of Chemical Biology
      • • Cancer Biology and Inflammatory Disorder Division (IICB)
      • • Infectious Diseases and Immunology Division (IICB)
      Kolkata, West Bengal, India
  • 2010
    • University of Rome Tor Vergata
      • Dipartimento di Biologia
      Roma, Latium, Italy
  • 2005
    • University of Texas Medical Branch at Galveston
      Galveston, Texas, United States
  • 2002
    • University of Virginia
      Charlottesville, Virginia, United States