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Malaria
and Other Parasitic Diseases |
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focus
on Malaria, Leishmania
and Filaria
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| Achievements |
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Drugs
commercialized |
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• |
(a)
Blood schizontocidal antimalarial E-Mal
(licenced to Themis India Ltd. since
1997) is a fast acting, semi-synthetic
artemisinin derivative effective against
drug resistant and cerebral malaria
cases. Post marketing surveillance shows
quick and sustained recovery of comatose
cerebral malaria cases and prevention
of high mortality. |
|
• |
(b)
Elubaquine an anti-relapse antimalarial
has been licenced to Nicholas Piramal
India Ltd. since 2000 for treatment
of relapses in P.vivax patients. Elubaquine
an analog of primaquine produces 3 to
4 times lower methemoglobin toxicity
thus providing an improved therapeutic
index over primaquine |
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Candidate
drugs under development |
• |
Compound
CDRI 97/78, a fully synthetic 1,2,4
trioxane derivative has been identified
for development as a viable alternative
to artemisinine derivatives for use
against drug resistant P. falciparum
and cerebral malaria cases. The compound
has successfully completed preclinical
efficacy and regulatory tests and Phase
I clinical trials are in progress |
• |
Another
antimalarial trioxane compound CDRI
99/411 with increased half life to allow
for extended exposure after oral dosage
has also completed preclinical efficacy
and regulatory studies. |
 ................... 
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| ...............................................CDRI 97/78 ............................................................................. CDRI 99/411 |
• |
Clinical development of both the above compounds
is being pursued under
Licensing agreements with IPCA Pharmaceuticals
Ltd., Mumbai. |
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| BASIC
RESEARCH |
Experimental
models
Modification of culture media constituents
enabling the use of Bovine serum in lieu of
scarcely available Human serum for in vitro
studies employing Plasmodium falciparum parasites.
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• |
An
experimental arteether resistant rodent
malaria model was established as a
tool to study mechanism of resistance.
Reporter gene based in vitro screening
assays employing GFP and Luciferase
transfected L. donovani parasites
established.
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| Pathway
and drug target identification |
• |
Targeting
of nuclear-encoded gyrase to the P.
falciparum apicoplast was established.
Interaction of a coumerin drug with
PfgyrB and inhibition of apicoplast
DNA replication was demonstrated.
Specific anti-parasitic effect of
inhibition of P. falciparum transketolase
identified the enzyme as a drug target. |
• |
B.
malayi hexokinase, trehalose 6-phosphate
synthase, independent phosphoglycerate
mutase and RNA helicase (Fig. below)
characterized as putative drug targets
against filaria. |
Three dimensional structure of BmL3-Helicase
|
• |
Leishmania
drug targets such as Pteridine reductase,
trypanothione reductase, dipetidyl
carboxypeptidase squalene synthase,
Hexokinase, Enolase, Aldolase and
Nucleoside diPhosphate Kinase b (NDKb)
investigated. |
• |
Biochemical
and molecular mechanism of drug resistance
studied in Leishmania; proteins/genes
identified in SAG resistant clinical
isolates. |
• |
DEAD
box RNA Helicase gene (BmL3-Helicase)
of B. malayi cloned, expressed, characterized
and validated by siRNA. |
• |
B. malayi
hexokinase (BmHK) cloned, expressed
and kinetic properties studied, 3D model
constructed. |
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| Molecular
and cell biology |
• |
Mechanism
of DNA replication and ori activation
of the P. falciparum apicoplast was
established. |
• |
Investigation
of apicoplast targeting and DNA condensation
properties of PfHU established the protein
as the major DNA organization protein
of the apicoplast genome. |
• |
The
role of actin and actin-related proteins
in Leishmania biology was established.
The role of coronin in regulation
of microtubule dynamics during cytokinesis
(Fig. below) and of ADF/cofilin in
actin-dynamics and flagellar assembly
in Leishmania was demonstrated. |
| |
 
Identification and Validation of Vaccine
Targets for their Prophylactic Potential
against Leishmania and Filaria |
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| Identification
and Validation of Vaccine Targets for their
Prophylactic Potential against Leishmania
and Filaria |
• |
Several
Th1 stimulatory Leishmania proteins
identified using proteomic approach
for their prophylactic potential. |
|
• |
Photodynamic
vaccination of hamsters with inducible
suicidal mutants of Leishmania
amazonensis elicited T cell-transferable
immunity against L. donovani
infection in hamsters. |
|
• |
Immunization
with the DNA Encoding N-terminal domain
of Proteophosphoglycan 3 of Leishmania
donovani generated Th-1 type
immuno-protective response against
experimental Visceral Leishmaniasis.
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|
• |
Recombinant
heavy chain myosin of B. malayi
induced significant protection against
infective larval challenge in rodents
through induction of mixed Th1/Th2
immune response. |
• |
Mitochondrial
fraction (MT) of adult B. malayi
contained proinflammatory molecules
which evoked a protective Th1 type
of immune response and the protection
was localized in the BMT-5 sub fraction.
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| Host-pathogen
interaction |
• |
Pro-inflammatory
molecules of B. malayi were
identified, purified and
characterized; their role in host-parasite
interactions established. |
• |
The
alterations in B. malayi
proteome pattern following Wolbachia
depletion after tetracycline
treatment established; proteins with
altered expression were analyzed.
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| Recent
Publications |
|
Malaria |
• |
Raghu
Ram EVS, Rangeetha Naik, Munia Ganguli
and Habib S (2008) DNA organization
by the apicoplast-targeted bacterial
histone-like protein of Plasmodium
falciparum. Nucleic Acids Research
36:5061-5073. |
• |
Sinha
S, Jha GN, Anand P, Qidwai T, Pati
SS, Mohanty S, Mishra SK, Tyagi PK,
Sharma SK, Venkatesh V, Habib S (2009).
CR1 levels and gene polymorphisms
exhibit differential association with
falciparum malaria in regions of varying
disease endemicity. Human Immunology
70: 244-250. |
• |
Kumar,
S., Guha, M., Choubey,V., Maity,P.,
Srivastava, K., Puri, S.K. and Bandyopadhyay,
U. (2008) Bilirubin inhibits Plasmodium
falciparum growth through the generation
of reactive oxygen species. Free Radic
Biol Med. 44, 602-613 |
• |
Madapa
S, Tusi Z, Mishra A, Srivastava K,
Pandey SK, Tripathi R, Puri SK, Batra
S.(2009) Search for new pharmacophores
for antimalarial activity. Part II:
synthesis and antimalarial activity
of new 6-ureido-4- anilinoquinazolines.
Bioorg Med Chem, 17(1):222-34, |
• |
Sharma
M, Chaturvedi V, Manju YK, Bhatnagar
S, Srivastava K, Puri SK, Chauhan,
PMS. (2009) Substituted quinolinyl
chalcones and quinolinyl pyrimidines
as a new class of anti-infective agents.
Eur J Med Chem. 44(5):2081-91. |
• |
Singh,
C., Verma, V.P, Naikade, NK, Singh,
A S, Hassam, M and Puri, SK (2008)
Novel Bis- and Tris-1,2,4 trioxanes:
Synthesis and antimalarial activity
against multi drug resistant P. yoelii
in Swiss mice. J. Med Chem., 51: 7581-92 |
• |
Dwivedi
V, Vasco A, Vedi S, Dangi A, Khan
A, Bhattacharya S M and Owais M (2009)
Adjuvanticity and protective immunity
of Plasmodium yoelii nigeriensis blood-stage
soluble antigens encapsulated in fusogenic
liposome. Vaccine 27: 473–482.
|
• |
Joshi
S, Singh AR, Kumar A, Misra PC, Siddiqi
MI and Saxena JK - Molecular cloning
and characterization of Plasmodium
falciparum transketolase (2008) -
Mol Biochem Parasitol. 160, 32-41 |
|
Filaria |
• |
Dangi
A, Vedi S, Nag JK, Pathinkar S, Singh
MP, Kar SK, Dube A, Bhattacharya SM
(2009) Tetracycline treatment targeting
Wolbachia affects expression of an array
of proteins in Brugia malayi parasite.
Proteomics 9: 4192–4208. |
• |
Sahoo
MK, Sisodia BS, Dixit S, Joseph SK,
Gaur RL, Verma SK, Verma AK, Shasany
AK, Dowle AA, Murthy PK (2009). Immunization
with inflammatory proteome of Brugia
malayi adult worm induces a Th1/Th2-immune
response and confers protection against
the filarial infection. Vaccine Jul
9; 27(32):4263-71. |
• |
Vedi
S, Dangi A, Hajela K and Misra-Bhattacharya
S (2008) Vaccination with 73 kDa recombinant
heavy chain myosin generates high level
of protection against Brugia malayi
challenge in jird and mastomys models.
Vaccine 26(47) 26: 5997-6005. |
• |
Singh
BK, Mishra M, Saxena N, Yadav GP, Maulik
PR, Sahoo MK, Gaur RL, Murthy PK, Tripathi
RP (2008) Synthesis of 2-sulfanyl-6-methyl-1,4-dihydropyrimidines
as a new class of antifilarial agents.
Eur J Med Chem. 43(12):2717-23. |
• |
Singh
AR, Joshi S, Arya R, Kayastha AM, Saxena
JK (2009) Guanidine hydrochloride and
urea induced unfolding of Brugia malayi
hexokinase. Euro Biophysics J. Sep 15.
[Epub ahead of print] |
• |
Meghna
Singh, Shilpy sakya, Vishal Kumar Soni,
Anil Dangi, Nikhil Kumar and S M Bhattacharya
(2009) The n-hexane and chloroform fractions
of Piper betle L. trigger different
arms of immune responses in BALB/c mice
and exhibit antifilarial activity against
human lymphatic filariid Brugia malayi..
Intern. Immunopharmacol. 6: 716-728. |
• |
Shakya
S, Singh PK, Kushwaha S and Bhattacharya
SM (2009) Adult Brugia malayi ~34kDa
(BMT-5) antigen offers Th1 mediated
significant protection against infective
larval challenge in Mastomys coucha.
Parasitol Internat. 58(4): 346-35. |
• |
Singh
AR, Joshi S, Arya R, Kayastha AM, Srivastava
KK, Tripathi LM, Saxena JK (2008) Molecular
cloning and characterization of Brugia
malayi hexokinase. Parasitol Int. 57(3):354-61.
|
• |
Kaushal,
N. A., Srivastava, N., Mustafa, H.,
Tandon, A., Singh, S. K. and Kaushal,
D. C. (2009). Isolation of an antigen
fraction from Setaria cervi adults having
potential for immunodiagnosis of human
filariasis. Immunol Invest 38 (8):749-61. |
• |
Murthy
PK, Dixit S, Gaur RL, Kumar R, Sahoo
MK, Shakya N, Joseph SK, Palne S, Gupta
S (2008) Influence of Brugia malayi
life stages and BmAFII fraction on experimental
Leishmania donovani infection in hamsters.
Acta Trop. 106(2):81-9. |
• |
Gaur
RL, Sahoo MK, Dixit S, Fatma N, Rastogi
S, Kulshreshtha DK, Chatterjee RK,
Murthy PK (2008).Antifilarial activity
of Caesalpinia bonducella against experimental
filarial infections. Indian J Med Res.
128(1):65-70. |
|
Leishmania |
• |
TV Tammana,
AA Sahasrabuddhe, K Mitra, VK Bajpai,
CMGupta (2008) Actin-depolymerizing
factor, ADF/cofilin, is essentially
required in assembly of Leishmania flagellum.
Mol. Microbiol. 70(4):837-52. |
• |
AA.
Sahasrabuddhe, RC. Nayak, CM. Gupta
(2009) Ancient Leishmania coronin (CRN12)
is involved in microtubule remodeling
during cytokinesis J. Cell Sci.122:1691. |
• |
R Kumar,
S Gupta, R Srivastava, AA Sahasrabuddhe,
CM Gupta (2009). Expression of a PTS2truncated
hexokinase produces glucose toxicity
in Leishmania donovani. Mol Biochem
Parasitol. 2009 Nov 16 ( in press) |
• |
SS Katta,
AA Sahasrabuddhe, CM Gupta. (2009).
Flagellar localization of a novel isoform
of myosin, myosin XXI, in Leishmania.
Mol Biochem Parasitol. 164:105-10. |
• |
P Kapoor,
AA Sahasrabuddhe, A Kumar, K Mitra,
MI Siddiqi, CM. Gupta (2008) An unconventional
form of actin in protozoan hemoflagellate,
Leishmania. J Biol Chem. 283:22760-73 |
• |
S Kumari,
M Samant, P Khare, P Misra, S Dutta,
BK Kolli, S Sharma, KP Chang, A Dube
(2009). Photodynamic vaccination of
hamsters with inducible suicidal mutants
of Leishmania amazonensis elicits T
cell-transferable immunity against visceral
leishmaniasis. Euro J Immunol 39:178-91.
|
• |
PP Pathak,
SV Pulavarti, A Jain, AA Sahasrabuddhe,
CM Gupta, A.Arora (2009) NMR assignment
of actin depolymerizing and dynamics
regulatory protein from Leishmania donovani.
Biomol NMR Assign.3:265-7. |
• |
M Samant,
R Gupta, S Kumari, P Misra, P Khare,
PK Kushawaha, AA Sahasrabuddhe, A Dube
(2009). Immunization with the DNA Encoding
N terminal domain of Proteophosphoglycan
3 of Leishmania donovani generates Th-1
type immuno-protective response against
Experimental Visceral Leishmaniasis,
J Immunol 183: 470-9. |
• |
N Singh,
R Gupta, A Dube (2009). Transgenic Leishmania
donovani clinical isolates expressing
GFP-constitutively for rapid and reliable
ex-vivo drug screening. J Antimicrob
Chemother, 64: 370-4. |
• |
N Singh,
J Kaur, P Kumar, S Gupta, N Singh, A
Ghosal, A Dutta, A Kumar, RP Tripathi,
MI Siddiqi, C Mandal, A Dube (2009).
An orally effective dihydropyrimidone
(DHPM) analogue induces apoptosis like
cell death in clinical isolates of Leishmania
donovani overexpressing pteridine reductase
1. Parasitology Research 105:1317-25.
|
• |
S Kumari,
M Samant, P Misra, P Khare, B Sisodia,
AK Shasany, A Dube (2008). Th1-stimulatory
polyproteins of soluble Leishmania donovani
promastigotes ranging from 89.9 to 97.1kDa
offers long-lasting protection against
experimental visceral leishmaniasis.
Vaccine. 26:5700-11. |
• |
S Kumari,
M Samant, P Khare, S Sundar, S Sinha,
A Dube (2008). Induction of Th1-type
cellular responses in cured/exposed
Leishmania infected patients and hamsters
against poly proteins of soluble Leishmania
donovani promastigotes ranging from
89.9-97.1 kDa. Vaccine 26:4813-8. |
• |
P Misra,
T Khaliq, A Dixit, S Sengupta, M Samant,
S Kumari, A Kumar, P Kushawaha, H Majumder,
AK Saxena, T Narender, A Dube (2008).
Antileishmanial activity mediated by
apoptosis and structure based target
study of Peganine hydrochloride dihydrate:
An approach for rational drug designing.
J Antimicrob Chemother 62 :998-1002.
|
• |
SK Gupta,
BS Sisodia, S Sinha, K Hajela, S Naik,
AK Shasany, A Dube (2007). Proteomic
approach for identification and characterization
of novel immunostimulatory proteins
from soluble antigens of Leishmania
donovani promastigotes. Proteomics 7,
816–823 |
• |
S Rai,
UN Dwivedi, N Goyal (2009). Leishmania
donovani trypanothione reductase: role
of urea and guanidine hydrochloride
in modulation of functional and structural
properties. Biochim Biophys Acta. 1794:1474-84 |
• |
R Vatsyayan,
U Roy. (2007). Molecular cloning and
biochemical characterization of Leishmania
donovani serine hydroxymethyltransferase.
Protein Expr Purif. ;52: 433-40 |
• |
J Kaur,
BK Singh, RP Tripathi, P Singh, N Singh.
(2009) Leishmania donovani: a glycosyl
dihydropyridine analogue induces apoptosis
like cell death via targeting pteridine
reductase 1 in promastigotes. Exp Parasitol.123:258-64. |
• |
P Kumar,
A Kumar, SS Verma, N Dwivedi, N Singh,
MI Siddiqi, RP Tripathi, A Dube, N Singh
(2008). Leishmania donovani pteridine
reductase 1: biochemical properties
and structure-modeling studies. Exp
Parasitol. 120:73-9. |
• |
Suryawanshi
SN, Chandra Naveen, Kumar Pawan, Porwal
Jyoti and Gupta Suman - Chemotherapy
of leishmaniasis part-VIII: Synthesis
and bioevaluation of novel chalcones
(2008) - Eur. J. Med. Chem. 43, 2473-2478 |
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