Asrar Alam - Academia.edu (original) (raw)
Papers by Asrar Alam
P. falciparum multistage viral-vectored vaccines effective for both sporozoite protection and transmission blocking
日本寄生虫学会大会プログラム・抄録集, 2017
Plasmodium falciparum serine repeat antigen 5 (SERA5) is a target for both drug and vaccine inter... more Plasmodium falciparum serine repeat antigen 5 (SERA5) is a target for both drug and vaccine intervention against malaria. SERA5 is secreted in the parasitophorous vacuole where it is proteolytically processed before schizont rupture. Among the processed products is a 50.8-kDa central domain of the protease, which possesses chymotrypsin-like activity and consists of a 28.9-kDa catalytic domain with a 21.9-kDa N-terminal prodomain, which remain attached together. Because SERA5 has been implicated in merozoite egress from host erythrocytes, the effect of the prodomain and a heptapeptide derived from its C-terminus spanning from D 560 to F 566 (DNSDNMF) on parasite growth was studied. When E. coli-expressed prodomain was incubated with parasite culture, a significant delay in transition from schizont to ring stages was observed up to nanomolar concentrations. The peptide, DNSDNMF also showed similar effects but at nearly 1000-fold higher concentrations. The peptide was also found to int...
Review Article Exploiting Unique Structural and Functional Properties of Malarial Glycolytic Enzymes for Antimalarial Drug Development
Copyright © 2014 Asrar Alam et al. This is an open access article distributed under the Creative ... more Copyright © 2014 Asrar Alam et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Metabolic enzymes have been known to carry out a variety of functions besides their normal housekeeping roles known as “moonlighting functions. ” These functionalities arise from structural changes induced by posttranslational modifications and/or binding of interacting proteins. Glycolysis is the sole source of energy generation for malaria parasite Plasmodium falciparum, hence a potential pathway for therapeutic intervention. Crystal structures of several P. falciparum glycolytic enzymes have been solved, revealing that they exhibit unique structural differences from the respective host enzymes, which could be exploited for their selective targeting. In addition, these enzymes carry out many parasite-specific functions, which could be ...
Molecular approaches to lung cancer prevention
Future oncology, 2021
Lung cancer is generally diagnosed at advanced stages when surgical resection is not possible. La... more Lung cancer is generally diagnosed at advanced stages when surgical resection is not possible. Late diagnosis, along with development of chemoresistance, results in high mortality. Preventive approaches, including smoking cessation, chemoprevention and early detection are needed to improve survival. Smoking cessation combined with low-dose computed tomography screening has modestly improved survival. Chemoprevention has also shown some promise. Despite these successes, most lung cancer cases remain undetected until advanced stages. Additional early detection strategies may further improve survival and treatment outcome. Molecular alterations taking place during lung carcinogenesis have the potential to be used in early detection via noninvasive methods and may also serve as biomarkers for success of chemopreventive approaches. This review focuses on the utilization of molecular biomarkers to increase the efficacy of various preventive approaches.
This is to certify that the research work embodied in this thesis entitled "Functional Chara... more This is to certify that the research work embodied in this thesis entitled "Functional Characterization of Subtilisin-like Protease 3 and Serine Repeat Antigen 5 from Plasmodium /alciparum" has been carried out in Malaria Research Group, International Centre for Genetic Engineering and Biotechnology, New Delhi. This work is original and no part of this thesis has been submitted for the award of any other degree or diploma to any other university.
Malaria is a major global parasitic disease responsible for tremendous health burden and mortalit... more Malaria is a major global parasitic disease responsible for tremendous health burden and mortality in tropical and subtropical regions of the world. Plasmodium falciparum is the causative agent of severe malaria, which accounts for most of the global malaria-related deaths, mainly in sub-Saharan Africa. Despite the enormous global efforts to curb the spread of the disease and significant decline in malaria-related deaths in the last decade, development of parasite resistance to currently used drugs is widespread, which necessitates the development of novel antimalarial targeting crucial parasite molecules. Parasite proteases are a group of molecules crucial for the development and propagation of the parasite inside the host cell. The major parasite-specific processes dependent on protease activity for their completion are hemoglobin degradation, merozoite egress from the host cell, and invasion of the host cells. A number of proteases of various classes are found in P. falciparum, m...
Therapeutic Potential of Phytoestrogens
Phytoestrogens are naturally occurring constituents of plants present in the significant proporti... more Phytoestrogens are naturally occurring constituents of plants present in the significant proportion of our diet. They have been extensively studied due to their potential as pharmacological targets and nutraceutical benefits. The potential pharmacological applications of these molecules include cardioprotection, antimicrobial, anticancer, anti-obesity, antiosteoporosis, antidiabetic, and neuroprotection. Phytoestrogens are polyphenolic nonsteroidal compounds of plant origin with estrogen-like biological activity. They mimic estradiol-like effects in several tissue/tissues of the mammalian body. The health benefits accredited to them are due to their ability to mimic estrogenic actions. In this chapter, we aim to provide comprehensive coverage of the pharmacological aspects of the most pronounced phytoestrogens of our daily life. We will discuss different classes of phytoestrogens under the subcategory of flavonoids and non-flavonoids. Numerous plant-derived compounds like genistein,...
Plasmodium falciparum apical membrane antigen 1 (PfAMA1) is a valuable vaccine candidate and expo... more Plasmodium falciparum apical membrane antigen 1 (PfAMA1) is a valuable vaccine candidate and exported on the merozoite surface at the time of erythrocyte invasion. PfAMA1 interacts with rhoptry neck protein PfRON2, a component of the rhoptry protein complex, which forms the tight junction at the time of invasion. Phage display studies have identified a 15-residue (F1) and a 20-residue (R1) peptide that bind to PfAMA1 and block the invasion of erythrocytes. Cocrystal structures of central region of PfAMA1 containing disulfide-linked clusters (domains I and II) with R1 peptide and a peptide derived from PfRON2 showed strong structural similarity in binding. The peptides bound to a hydrophobic groove surrounded by domain I and II loops. In this study, peptidomimetics based on the crucial PfAMA1-binding residues of PfRON2 peptide have been identified. Top 5 peptidomimetics when checked for their docking on the region of PfAMA1 encompassing the hydrophobic groove were found to dock on th...
Recent Nano-based therapeutic intervention of Bioactive Sesquiterpenes: Prospects in cancer therapeutics
Current Pharmaceutical Design
: In recent scenario, nanotechnology based therapeutics intervention has gained tremendous impetu... more : In recent scenario, nanotechnology based therapeutics intervention has gained tremendous impetus all across the globe. Nano-based pharmacological intervention of various bioactive compounds has been explored on an increasing scale. Sesquiterpenes are major constituents of essential oils (EOs) present in various plant species which embodies intriguing therapeutic potentials. However, owing to their poor physico-chemical properties; they have pharmacological limitations. Recent advances in nano-based therapeutic interventions offer various avenues to improve their therapeutic applicability. Reckoning with these, the present review collates various nano-based therapeutic intervention of sesquiterpenes with prospective potential against various debilitating diseases especially cancer. In our viewpoint, considering the burgeoning advancement in the field of nanomedicine; in the near future, clinical applicability of these nano-formulated sesquiterpenes can be foreseen with great enthusiasm.
ABSTRACTBaculovirus (BV), an enveloped insect virus with a circular double-stranded DNA genome, p... more ABSTRACTBaculovirus (BV), an enveloped insect virus with a circular double-stranded DNA genome, possesses unique characteristics that induce strong innate immune responses in mammalian cells. Here, we show that BV administration not only sterilely protects BALB/c mice for at least 7 days from subsequent Plasmodium berghei sporozoite infection but also eliminates existing liver-stage parasites completely, effects superior to those of primaquine, and does so in a TLR9-independent manner. Six hours post-BV administration, IFN-α and IFN-γ were robustly produced in serum, and RNA transcripts of interferon-stimulated genes were drastically upregulated in the liver. The in vivo passive transfer of post-BV administration serum effectively eliminated liver-stage parasites, and IFN-α neutralization abolished this effect, indicating that the BV liver-stage parasite killing mechanism is downstream of the type I IFN signaling pathway. Our results demonstrate that BV is a potent IFN-inducing prop...
Plasmodium falciparum serine repeat antigen 5 (SERA5) is a target for both drug and vaccine inter... more Plasmodium falciparum serine repeat antigen 5 (SERA5) is a target for both drug and vaccine intervention against malaria. SERA5 is secreted in the parasitophorous vacuole where it is proteolytically processed before schizont rupture. Among the processed products is a 50.8-kDa central domain of the protease, which possesses chymotrypsin-like activity and consists of a 28.9-kDa catalytic domain with a 21.9-kDa N-terminal prodomain, which remain attached together. Because SERA5 has been implicated in merozoite egress from host erythrocytes, the effect of the prodomain and a heptapeptide derived from its C-terminus spanning from D 560 to F 566 (DNSDNMF) on parasite growth was studied. When E. coli-expressed prodomain was incubated with parasite culture, a significant delay in transition from schizont to ring stages was observed up to nanomolar concentrations. The peptide, DNSDNMF also showed similar effects but at nearly 1000-fold higher concentrations. The peptide was also found to interact with the catalytic domain. These data demonstrate the crucial role of SERA5 prodomain for the egress process. Given the inhibitory potential of the prodomain for the parasite, we suggest that peptidomimetic inhibitors based on SERA5 prodomain sequences can be developed as future therapeutics against malaria.
Background: Chloroquine (CQ)-resistant Plasmodium falciparum malaria has been a global health cat... more Background: Chloroquine (CQ)-resistant Plasmodium falciparum malaria has been a global health catastrophe, yet much about the CQ resistance (CQR) mechanism remains unclear. Hallmarks of the CQR phenotype include reduced accumulation of protonated CQ as a weak base in the digestive vacuole of the erythrocyte-stage parasite, and chemosensitization of CQresistant (but not CQ-sensitive) P. falciparum by agents such as verapamil. Mutations in the P. falciparum CQR transporter (PfCRT) confer CQR; particularly important among these mutations is the charge-loss substitution KRT at position 76. Dictyostelium discoideum transformed with mutant PfCRT expresses key features of CQR including reduced drug accumulation and verapamil chemosensitization. Methodology and Findings: We describe the isolation and characterization of PfCRT-transformed, hematin-free vesicles from D. discoideum cells. These vesicles permit assessments of drug accumulation, pH, and membrane potential that are difficult or impossible with hematin-containing digestive vacuoles from P. falciparum-infected erythrocytes. Mutant PfCRTtransformed D. discoideum vesicles show features of the CQR phenotype, and manipulations of vesicle membrane potential by agents including ionophores produce large changes of CQ accumulation that are dissociated from vesicular pH. PfCRT in its native or mutant form blunts the ability of valinomycin to reduce CQ accumulation in transformed vesicles and decreases the ability of K + to reverse membrane potential hyperpolarization caused by valinomycin treatment. Conclusion: Isolated vesicles from mutant-PfCRT-transformed D. discoideum exhibit features of the CQR phenotype, consistent with evidence that the drug resistance mechanism operates at the P. falciparum digestive vacuole membrane in malaria. Membrane potential apart from pH has a major effect on the PfCRT-mediated CQR phenotype of D. discoideum vesicles. These results support a model of PfCRT as an electrochemical potential-driven transporter in the drug/metabolite superfamily that (appropriately mutated) acts as a saturable simple carrier for the facilitated diffusion of protonated CQ.
HTTP://HERMES.MBL.EDU/MPM/MPM-2011/ABSTRACTS/ABSTRACT.PHP?ID=68
In silico Analysis of Plasmodium falciparum Actin and Profilin Interaction at the Interface Region for Antimalarial Drug Designing
Letters in Drug Design & Discovery, 2015
In Silico Analysis of Plasmodium Falciparumenolase and Human Plasminogen Interaction: Implications for Transmission blocking of the Parasite
Letters in Drug Design & Discovery, 2015
Malaria Research and Treatment, 2014
Plasmodium falciparumapical membrane antigen 1 (PfAMA1) is a valuable vaccine candidate and expor... more Plasmodium falciparumapical membrane antigen 1 (PfAMA1) is a valuable vaccine candidate and exported on the merozoite surface at the time of erythrocyte invasion. PfAMA1 interacts with rhoptry neck protein PfRON2, a component of the rhoptry protein complex, which forms the tight junction at the time of invasion. Phage display studies have identified a 15-residue (F1) and a 20-residue (R1) peptide that bind to PfAMA1 and block the invasion of erythrocytes. Cocrystal structures of central region of PfAMA1 containing disulfide-linked clusters (domains I and II) with R1 peptide and a peptide derived from PfRON2 showed strong structural similarity in binding. The peptides bound to a hydrophobic groove surrounded by domain I and II loops. In this study, peptidomimetics based on the crucial PfAMA1-binding residues of PfRON2 peptide have been identified. Top 5 peptidomimetics when checked for their docking on the region of PfAMA1 encompassing the hydrophobic groove were found to dock on the...
Interdisciplinary Perspectives on Infectious Diseases, 2014
Malaria is a major global parasitic disease and a cause of enormous mortality and morbidity. Wide... more Malaria is a major global parasitic disease and a cause of enormous mortality and morbidity. Widespread drug resistance against currently available antimalarials warrants the identification of novel drug targets and development of new drugs. Malarial proteases are a group of molecules that serve as potential drug targets because of their essentiality for parasite life cycle stages and feasibility of designing specific inhibitors against them. Proteases belonging to various mechanistic classes are found inP. falciparum, of which serine proteases are of particular interest due to their involvement in parasite-specific processes of egress and invasion. InP. falciparum, a number of serine proteases belonging to chymotrypsin, subtilisin, and rhomboid clans are found. This review focuses on the potential ofP. falciparumserine proteases as antimalarial drug targets.
PLoS ONE, 2012
Plasmodium falciparum serine repeat antigen 5 (SERA5) is a target for both drug and vaccine inter... more Plasmodium falciparum serine repeat antigen 5 (SERA5) is a target for both drug and vaccine intervention against malaria. SERA5 is secreted in the parasitophorous vacuole where it is proteolytically processed before schizont rupture. Among the processed products is a 50.8-kDa central domain of the protease, which possesses chymotrypsin-like activity and consists of a 28.9-kDa catalytic domain with a 21.9-kDa N-terminal prodomain, which remain attached together. Because SERA5 has been implicated in merozoite egress from host erythrocytes, the effect of the prodomain and a heptapeptide derived from its C-terminus spanning from D 560 to F 566 (DNSDNMF) on parasite growth was studied. When E. coli-expressed prodomain was incubated with parasite culture, a significant delay in transition from schizont to ring stages was observed up to nanomolar concentrations. The peptide, DNSDNMF also showed similar effects but at nearly 1000-fold higher concentrations. The peptide was also found to interact with the catalytic domain. These data demonstrate the crucial role of SERA5 prodomain for the egress process. Given the inhibitory potential of the prodomain for the parasite, we suggest that peptidomimetic inhibitors based on SERA5 prodomain sequences can be developed as future therapeutics against malaria.
Malaria Research and Treatment, 2014
Metabolic enzymes have been known to carry out a variety of functions besides their normal housek... more Metabolic enzymes have been known to carry out a variety of functions besides their normal housekeeping roles known as “moonlighting functions.” These functionalities arise from structural changes induced by posttranslational modifications and/or binding of interacting proteins. Glycolysis is the sole source of energy generation for malaria parasitePlasmodium falciparum, hence a potential pathway for therapeutic intervention. Crystal structures of severalP. falciparumglycolytic enzymes have been solved, revealing that they exhibit unique structural differences from the respective host enzymes, which could be exploited for their selective targeting. In addition, these enzymes carry out many parasite-specific functions, which could be of potential interest to control parasite development and transmission. This review focuses on the moonlighting functions ofP. falciparumglycolytic enzymes and unique structural differences and functional features of the parasite enzymes, which could be ...
P. falciparum multistage viral-vectored vaccines effective for both sporozoite protection and transmission blocking
日本寄生虫学会大会プログラム・抄録集, 2017
Plasmodium falciparum serine repeat antigen 5 (SERA5) is a target for both drug and vaccine inter... more Plasmodium falciparum serine repeat antigen 5 (SERA5) is a target for both drug and vaccine intervention against malaria. SERA5 is secreted in the parasitophorous vacuole where it is proteolytically processed before schizont rupture. Among the processed products is a 50.8-kDa central domain of the protease, which possesses chymotrypsin-like activity and consists of a 28.9-kDa catalytic domain with a 21.9-kDa N-terminal prodomain, which remain attached together. Because SERA5 has been implicated in merozoite egress from host erythrocytes, the effect of the prodomain and a heptapeptide derived from its C-terminus spanning from D 560 to F 566 (DNSDNMF) on parasite growth was studied. When E. coli-expressed prodomain was incubated with parasite culture, a significant delay in transition from schizont to ring stages was observed up to nanomolar concentrations. The peptide, DNSDNMF also showed similar effects but at nearly 1000-fold higher concentrations. The peptide was also found to int...
Review Article Exploiting Unique Structural and Functional Properties of Malarial Glycolytic Enzymes for Antimalarial Drug Development
Copyright © 2014 Asrar Alam et al. This is an open access article distributed under the Creative ... more Copyright © 2014 Asrar Alam et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Metabolic enzymes have been known to carry out a variety of functions besides their normal housekeeping roles known as “moonlighting functions. ” These functionalities arise from structural changes induced by posttranslational modifications and/or binding of interacting proteins. Glycolysis is the sole source of energy generation for malaria parasite Plasmodium falciparum, hence a potential pathway for therapeutic intervention. Crystal structures of several P. falciparum glycolytic enzymes have been solved, revealing that they exhibit unique structural differences from the respective host enzymes, which could be exploited for their selective targeting. In addition, these enzymes carry out many parasite-specific functions, which could be ...
Molecular approaches to lung cancer prevention
Future oncology, 2021
Lung cancer is generally diagnosed at advanced stages when surgical resection is not possible. La... more Lung cancer is generally diagnosed at advanced stages when surgical resection is not possible. Late diagnosis, along with development of chemoresistance, results in high mortality. Preventive approaches, including smoking cessation, chemoprevention and early detection are needed to improve survival. Smoking cessation combined with low-dose computed tomography screening has modestly improved survival. Chemoprevention has also shown some promise. Despite these successes, most lung cancer cases remain undetected until advanced stages. Additional early detection strategies may further improve survival and treatment outcome. Molecular alterations taking place during lung carcinogenesis have the potential to be used in early detection via noninvasive methods and may also serve as biomarkers for success of chemopreventive approaches. This review focuses on the utilization of molecular biomarkers to increase the efficacy of various preventive approaches.
This is to certify that the research work embodied in this thesis entitled "Functional Chara... more This is to certify that the research work embodied in this thesis entitled "Functional Characterization of Subtilisin-like Protease 3 and Serine Repeat Antigen 5 from Plasmodium /alciparum" has been carried out in Malaria Research Group, International Centre for Genetic Engineering and Biotechnology, New Delhi. This work is original and no part of this thesis has been submitted for the award of any other degree or diploma to any other university.
Malaria is a major global parasitic disease responsible for tremendous health burden and mortalit... more Malaria is a major global parasitic disease responsible for tremendous health burden and mortality in tropical and subtropical regions of the world. Plasmodium falciparum is the causative agent of severe malaria, which accounts for most of the global malaria-related deaths, mainly in sub-Saharan Africa. Despite the enormous global efforts to curb the spread of the disease and significant decline in malaria-related deaths in the last decade, development of parasite resistance to currently used drugs is widespread, which necessitates the development of novel antimalarial targeting crucial parasite molecules. Parasite proteases are a group of molecules crucial for the development and propagation of the parasite inside the host cell. The major parasite-specific processes dependent on protease activity for their completion are hemoglobin degradation, merozoite egress from the host cell, and invasion of the host cells. A number of proteases of various classes are found in P. falciparum, m...
Therapeutic Potential of Phytoestrogens
Phytoestrogens are naturally occurring constituents of plants present in the significant proporti... more Phytoestrogens are naturally occurring constituents of plants present in the significant proportion of our diet. They have been extensively studied due to their potential as pharmacological targets and nutraceutical benefits. The potential pharmacological applications of these molecules include cardioprotection, antimicrobial, anticancer, anti-obesity, antiosteoporosis, antidiabetic, and neuroprotection. Phytoestrogens are polyphenolic nonsteroidal compounds of plant origin with estrogen-like biological activity. They mimic estradiol-like effects in several tissue/tissues of the mammalian body. The health benefits accredited to them are due to their ability to mimic estrogenic actions. In this chapter, we aim to provide comprehensive coverage of the pharmacological aspects of the most pronounced phytoestrogens of our daily life. We will discuss different classes of phytoestrogens under the subcategory of flavonoids and non-flavonoids. Numerous plant-derived compounds like genistein,...
Plasmodium falciparum apical membrane antigen 1 (PfAMA1) is a valuable vaccine candidate and expo... more Plasmodium falciparum apical membrane antigen 1 (PfAMA1) is a valuable vaccine candidate and exported on the merozoite surface at the time of erythrocyte invasion. PfAMA1 interacts with rhoptry neck protein PfRON2, a component of the rhoptry protein complex, which forms the tight junction at the time of invasion. Phage display studies have identified a 15-residue (F1) and a 20-residue (R1) peptide that bind to PfAMA1 and block the invasion of erythrocytes. Cocrystal structures of central region of PfAMA1 containing disulfide-linked clusters (domains I and II) with R1 peptide and a peptide derived from PfRON2 showed strong structural similarity in binding. The peptides bound to a hydrophobic groove surrounded by domain I and II loops. In this study, peptidomimetics based on the crucial PfAMA1-binding residues of PfRON2 peptide have been identified. Top 5 peptidomimetics when checked for their docking on the region of PfAMA1 encompassing the hydrophobic groove were found to dock on th...
Recent Nano-based therapeutic intervention of Bioactive Sesquiterpenes: Prospects in cancer therapeutics
Current Pharmaceutical Design
: In recent scenario, nanotechnology based therapeutics intervention has gained tremendous impetu... more : In recent scenario, nanotechnology based therapeutics intervention has gained tremendous impetus all across the globe. Nano-based pharmacological intervention of various bioactive compounds has been explored on an increasing scale. Sesquiterpenes are major constituents of essential oils (EOs) present in various plant species which embodies intriguing therapeutic potentials. However, owing to their poor physico-chemical properties; they have pharmacological limitations. Recent advances in nano-based therapeutic interventions offer various avenues to improve their therapeutic applicability. Reckoning with these, the present review collates various nano-based therapeutic intervention of sesquiterpenes with prospective potential against various debilitating diseases especially cancer. In our viewpoint, considering the burgeoning advancement in the field of nanomedicine; in the near future, clinical applicability of these nano-formulated sesquiterpenes can be foreseen with great enthusiasm.
ABSTRACTBaculovirus (BV), an enveloped insect virus with a circular double-stranded DNA genome, p... more ABSTRACTBaculovirus (BV), an enveloped insect virus with a circular double-stranded DNA genome, possesses unique characteristics that induce strong innate immune responses in mammalian cells. Here, we show that BV administration not only sterilely protects BALB/c mice for at least 7 days from subsequent Plasmodium berghei sporozoite infection but also eliminates existing liver-stage parasites completely, effects superior to those of primaquine, and does so in a TLR9-independent manner. Six hours post-BV administration, IFN-α and IFN-γ were robustly produced in serum, and RNA transcripts of interferon-stimulated genes were drastically upregulated in the liver. The in vivo passive transfer of post-BV administration serum effectively eliminated liver-stage parasites, and IFN-α neutralization abolished this effect, indicating that the BV liver-stage parasite killing mechanism is downstream of the type I IFN signaling pathway. Our results demonstrate that BV is a potent IFN-inducing prop...
Plasmodium falciparum serine repeat antigen 5 (SERA5) is a target for both drug and vaccine inter... more Plasmodium falciparum serine repeat antigen 5 (SERA5) is a target for both drug and vaccine intervention against malaria. SERA5 is secreted in the parasitophorous vacuole where it is proteolytically processed before schizont rupture. Among the processed products is a 50.8-kDa central domain of the protease, which possesses chymotrypsin-like activity and consists of a 28.9-kDa catalytic domain with a 21.9-kDa N-terminal prodomain, which remain attached together. Because SERA5 has been implicated in merozoite egress from host erythrocytes, the effect of the prodomain and a heptapeptide derived from its C-terminus spanning from D 560 to F 566 (DNSDNMF) on parasite growth was studied. When E. coli-expressed prodomain was incubated with parasite culture, a significant delay in transition from schizont to ring stages was observed up to nanomolar concentrations. The peptide, DNSDNMF also showed similar effects but at nearly 1000-fold higher concentrations. The peptide was also found to interact with the catalytic domain. These data demonstrate the crucial role of SERA5 prodomain for the egress process. Given the inhibitory potential of the prodomain for the parasite, we suggest that peptidomimetic inhibitors based on SERA5 prodomain sequences can be developed as future therapeutics against malaria.
Background: Chloroquine (CQ)-resistant Plasmodium falciparum malaria has been a global health cat... more Background: Chloroquine (CQ)-resistant Plasmodium falciparum malaria has been a global health catastrophe, yet much about the CQ resistance (CQR) mechanism remains unclear. Hallmarks of the CQR phenotype include reduced accumulation of protonated CQ as a weak base in the digestive vacuole of the erythrocyte-stage parasite, and chemosensitization of CQresistant (but not CQ-sensitive) P. falciparum by agents such as verapamil. Mutations in the P. falciparum CQR transporter (PfCRT) confer CQR; particularly important among these mutations is the charge-loss substitution KRT at position 76. Dictyostelium discoideum transformed with mutant PfCRT expresses key features of CQR including reduced drug accumulation and verapamil chemosensitization. Methodology and Findings: We describe the isolation and characterization of PfCRT-transformed, hematin-free vesicles from D. discoideum cells. These vesicles permit assessments of drug accumulation, pH, and membrane potential that are difficult or impossible with hematin-containing digestive vacuoles from P. falciparum-infected erythrocytes. Mutant PfCRTtransformed D. discoideum vesicles show features of the CQR phenotype, and manipulations of vesicle membrane potential by agents including ionophores produce large changes of CQ accumulation that are dissociated from vesicular pH. PfCRT in its native or mutant form blunts the ability of valinomycin to reduce CQ accumulation in transformed vesicles and decreases the ability of K + to reverse membrane potential hyperpolarization caused by valinomycin treatment. Conclusion: Isolated vesicles from mutant-PfCRT-transformed D. discoideum exhibit features of the CQR phenotype, consistent with evidence that the drug resistance mechanism operates at the P. falciparum digestive vacuole membrane in malaria. Membrane potential apart from pH has a major effect on the PfCRT-mediated CQR phenotype of D. discoideum vesicles. These results support a model of PfCRT as an electrochemical potential-driven transporter in the drug/metabolite superfamily that (appropriately mutated) acts as a saturable simple carrier for the facilitated diffusion of protonated CQ.
HTTP://HERMES.MBL.EDU/MPM/MPM-2011/ABSTRACTS/ABSTRACT.PHP?ID=68
In silico Analysis of Plasmodium falciparum Actin and Profilin Interaction at the Interface Region for Antimalarial Drug Designing
Letters in Drug Design & Discovery, 2015
In Silico Analysis of Plasmodium Falciparumenolase and Human Plasminogen Interaction: Implications for Transmission blocking of the Parasite
Letters in Drug Design & Discovery, 2015
Malaria Research and Treatment, 2014
Plasmodium falciparumapical membrane antigen 1 (PfAMA1) is a valuable vaccine candidate and expor... more Plasmodium falciparumapical membrane antigen 1 (PfAMA1) is a valuable vaccine candidate and exported on the merozoite surface at the time of erythrocyte invasion. PfAMA1 interacts with rhoptry neck protein PfRON2, a component of the rhoptry protein complex, which forms the tight junction at the time of invasion. Phage display studies have identified a 15-residue (F1) and a 20-residue (R1) peptide that bind to PfAMA1 and block the invasion of erythrocytes. Cocrystal structures of central region of PfAMA1 containing disulfide-linked clusters (domains I and II) with R1 peptide and a peptide derived from PfRON2 showed strong structural similarity in binding. The peptides bound to a hydrophobic groove surrounded by domain I and II loops. In this study, peptidomimetics based on the crucial PfAMA1-binding residues of PfRON2 peptide have been identified. Top 5 peptidomimetics when checked for their docking on the region of PfAMA1 encompassing the hydrophobic groove were found to dock on the...
Interdisciplinary Perspectives on Infectious Diseases, 2014
Malaria is a major global parasitic disease and a cause of enormous mortality and morbidity. Wide... more Malaria is a major global parasitic disease and a cause of enormous mortality and morbidity. Widespread drug resistance against currently available antimalarials warrants the identification of novel drug targets and development of new drugs. Malarial proteases are a group of molecules that serve as potential drug targets because of their essentiality for parasite life cycle stages and feasibility of designing specific inhibitors against them. Proteases belonging to various mechanistic classes are found inP. falciparum, of which serine proteases are of particular interest due to their involvement in parasite-specific processes of egress and invasion. InP. falciparum, a number of serine proteases belonging to chymotrypsin, subtilisin, and rhomboid clans are found. This review focuses on the potential ofP. falciparumserine proteases as antimalarial drug targets.
PLoS ONE, 2012
Plasmodium falciparum serine repeat antigen 5 (SERA5) is a target for both drug and vaccine inter... more Plasmodium falciparum serine repeat antigen 5 (SERA5) is a target for both drug and vaccine intervention against malaria. SERA5 is secreted in the parasitophorous vacuole where it is proteolytically processed before schizont rupture. Among the processed products is a 50.8-kDa central domain of the protease, which possesses chymotrypsin-like activity and consists of a 28.9-kDa catalytic domain with a 21.9-kDa N-terminal prodomain, which remain attached together. Because SERA5 has been implicated in merozoite egress from host erythrocytes, the effect of the prodomain and a heptapeptide derived from its C-terminus spanning from D 560 to F 566 (DNSDNMF) on parasite growth was studied. When E. coli-expressed prodomain was incubated with parasite culture, a significant delay in transition from schizont to ring stages was observed up to nanomolar concentrations. The peptide, DNSDNMF also showed similar effects but at nearly 1000-fold higher concentrations. The peptide was also found to interact with the catalytic domain. These data demonstrate the crucial role of SERA5 prodomain for the egress process. Given the inhibitory potential of the prodomain for the parasite, we suggest that peptidomimetic inhibitors based on SERA5 prodomain sequences can be developed as future therapeutics against malaria.
Malaria Research and Treatment, 2014
Metabolic enzymes have been known to carry out a variety of functions besides their normal housek... more Metabolic enzymes have been known to carry out a variety of functions besides their normal housekeeping roles known as “moonlighting functions.” These functionalities arise from structural changes induced by posttranslational modifications and/or binding of interacting proteins. Glycolysis is the sole source of energy generation for malaria parasitePlasmodium falciparum, hence a potential pathway for therapeutic intervention. Crystal structures of severalP. falciparumglycolytic enzymes have been solved, revealing that they exhibit unique structural differences from the respective host enzymes, which could be exploited for their selective targeting. In addition, these enzymes carry out many parasite-specific functions, which could be of potential interest to control parasite development and transmission. This review focuses on the moonlighting functions ofP. falciparumglycolytic enzymes and unique structural differences and functional features of the parasite enzymes, which could be ...