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Daniel E. Goldberg - One of the best experts on this subject based on the ideXlab platform.
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New benzimidazole derivatives as antiplasmodial agents and Plasmepsin inhibitors: Synthesis and analysis of structure-activity relationships
Bioorganic and Medicinal Chemistry Letters, 2012Co-Authors: Zafar Saied Saify, SHAHNAZ AKHTAR, Shaheen A. Hussain, Arshad Arayne, Mehrun Nisa, Aftab Akram, M. Kamran Azim, Daniel E. Goldberg, Waseem Ahmad, A OksmanAbstract:The newly synthesized benzimidazole compounds were suggested to be inhibitors of Plasmodium falciparum Plasmepsin II and human cathepsin D by virtual screening of an internal library of synthetic compounds. This was confirmed by enzyme inhibition studies that gave IC 50 values in the low micromolar range (2-48 μM). Ligand docking studies with Plasmepsin II predicted binding of benzimidazole compounds at the center of the extended substrate-binding cleft. According to the plausible mode of binding, the pyridine ring of benzimidazole compounds interacted with S1′ subsite residues whereas the acetophenone moiety was in contact with S1-S3 subsites of Plasmepsin II active center. The benzimidazole derivatives were evaluated for capacity to inhibit the growth of intraerythrocytic P. falciparum in culture. Four benzimidazole compounds inhibited parasite growth at ≤3 μM. The most active compound 10, 1-(4-phenylphenyl)-2[2-(pyridinyl-2-yl)-1,3-benzdiazol-1-yl] ethanone showed an IC 50 of 160 nM. The substitution of a phenyl group and a chlorine atom at the para position of the acetophenone moiety were shown to be crucial for antiplasmodial activity. © 2011 Elsevier Ltd. All rights reserved.
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New benzimidazole derivatives as antiplasmodial agents and Plasmepsin inhibitors: Synthesis and analysis of structure–activity relationships
Bioorganic & Medicinal Chemistry Letters, 2011Co-Authors: Zafar Saied Saify, Shaheen A. Hussain, Arshad Arayne, Mehrun Nisa, M. Kamran Azim, Daniel E. Goldberg, Waseem Ahmad, Shamim Akhtar, Arfa Akram, Anna OksmanAbstract:Abstract The newly synthesized benzimidazole compounds were suggested to be inhibitors of Plasmodium falciparum Plasmepsin II and human cathepsin D by virtual screening of an internal library of synthetic compounds. This was confirmed by enzyme inhibition studies that gave IC50 values in the low micromolar range (2–48 μM). Ligand docking studies with Plasmepsin II predicted binding of benzimidazole compounds at the center of the extended substrate-binding cleft. According to the plausible mode of binding, the pyridine ring of benzimidazole compounds interacted with S1′ subsite residues whereas the acetophenone moiety was in contact with S1–S3 subsites of Plasmepsin II active center. The benzimidazole derivatives were evaluated for capacity to inhibit the growth of intraerythrocytic P. falciparum in culture. Four benzimidazole compounds inhibited parasite growth at ⩽3 μM. The most active compound 10, 1-(4-phenylphenyl)-2[2-(pyridinyl-2-yl)-1,3-benzdiazol-1-yl]ethanone showed an IC50 of 160 nM. The substitution of a phenyl group and a chlorine atom at the para position of the acetophenone moiety were shown to be crucial for antiplasmodial activity.
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hemoglobin degrading Plasmepsin II is active as a monomer
Journal of Biological Chemistry, 2006Co-Authors: Eva S Istvan, Daniel E. GoldbergAbstract:Abstract A family of aspartic proteases called Plasmepsins is important for hemoglobin degradation in intraerythrocytic Plasmodium parasites. Plasmepsin II (PM II) is the best studied member of this family. PM II and its close orthologs and paralogs form homodimers with extensive interfaces in all known crystal structures. This raised the question whether the homodimer is the functional subunit of Plasmepsins in solution. We have used gel filtration chromatography, site-directed mutagenesis, and analytical ultracentrifugation to study the oligomeric status of PM II in solution. Our results reveal that PM II exists mainly as a monomer in solution and that the monomer is fully functional for catalysis. A hydrophobic loop at the PM II monomer surface, which would be buried in a PM II dimer, is shown to be essential for the hemoglobin degradation capability of PM II.
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Antimalarial Activity of Human Immunodeficiency Virus Type 1 Protease Inhibitors
Antimicrobial Agents and Chemotherapy, 2005Co-Authors: Sunil Parikh, Daniel E. Goldberg, Eva S Istvan, Diane V. Havlir, Philip J. RosenthalAbstract:Aspartic proteases play key roles in the biology of malaria parasites and human immunodeficiency virus type 1 (HIV-1). We tested the activity of seven HIV-1 protease inhibitors against cultured Plasmodium falciparum. All compounds inhibited the development of parasites at pharmacologically relevant concentrations. The most potent compound, lopinavir, was active against parasites (50% inhibitory concentration [IC50], 0.9 to 2.1 μM) at concentrations well below those achieved by ritonavir-boosted lopinavir therapy. Lopinavir also inhibited the P. falciparum aspartic protease Plasmepsin II at a similar concentration (IC50, 2.7 μM). These findings suggest that use of HIV-1 protease inhibitors may offer clinically relevant antimalarial activity.
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trafficking of Plasmepsin II to the food vacuole of the malaria parasite plasmodium falciparum
Journal of Cell Biology, 2004Co-Authors: Michael Klemba, Ilya Y Gluzman, Wandy L Beatty, Daniel E. GoldbergAbstract:fA amily of aspartic proteases, the Plasmepsins (PMs), plays a key role in the degradation of hemoglobin in the Plasmodium falciparum food vacuole. To study the trafficking of proPM II, we have modified the chromosomal PM II gene in P. falciparum to encode a proPM II–GFP chimera. By taking advantage of green fluorescent protein fluorescence in live parasites, the ultrastructural resolution of immunoelectron microscopy, and inhibitors of trafficking and PM maturation, we have investigated the biosynthetic path leading to mature PM II in the food vacuole. Our data support a model whereby proPM II is transported through the secretory system to cytostomal vacuoles and then is carried along with its substrate hemoglobin to the food vacuole where it is proteolytically processed to mature PM II.
Rickey Y Yada - One of the best experts on this subject based on the ideXlab platform.
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the prosegment catalyzes native folding of plasmodium falciparum Plasmepsin II
Biochimica et Biophysica Acta, 2016Co-Authors: Ahmad Haniff Jaafar, Huogen Xiao, Brian C Bryksa, Prasenjit Bhaumik, Rickey Y YadaAbstract:Plasmepsin II is a malarial pepsin-like aspartic protease produced as a zymogen containing an N-terminal prosegment domain that is removed during activation. Despite structural similarities between active Plasmepsin II and pepsin, their prosegments adopt different conformations in the respective zymogens. In contrast to pepsinogen, the proPlasmepsin II prosegment is 80 residues longer, contains a transmembrane region and is non-essential for recombinant expression in an active form, thus calling into question the prosegment's precise function. The present study examines the role of the prosegment in the folding mechanism of Plasmepsin II. Both a shorter (residues 77–124) and a longer (residues 65–124) prosegment catalyze Plasmepsin II folding at rates more than four orders of magnitude faster compared to folding without prosegment. Native Plasmepsin II is kinetically trapped and requires the prosegment both to catalyze folding and to shift the folding equilibrium towards the native conformation. Thus, despite low sequence identity and distinct zymogen conformations, the folding landscapes of Plasmepsin II and pepsin, both with and without prosegment, are qualitatively identical. These results imply a conserved and unusual feature of the pepsin-like protease topology that necessitates prosegment-assisted folding.
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the native conformation of Plasmepsin II is kinetically trapped at neutral ph
Archives of Biochemistry and Biophysics, 2011Co-Authors: Huogen Xiao, Rickey Y YadaAbstract:Abstract Plasmepsin II (PMII), an aspartic protease from the malarial parasite Plasmodium falciparum , represents a model for understanding protease structure/function relationships due to its unique structure and properties. The present study undertook a thermodynamic and kinetic analysis of the PMII folding mechanism and a pH stability profile. Differential scanning calorimetry revealed that the native state of PMII (Np) was irreversibly unfolded, and in the pH range of 6.5–8.0, PMII refolds to a denatured state (Rp) with higher thermal stability than Np. Rp could also be formed upon partially unfolding PMII at pH 11.0 and 37 °C for 2 h, followed by adjustment to a pH in the range of 6.5–8.0. While Rp could be folded/unfolded reversibly, Np was shown to exist as a kinetically trapped state. By examining the unfolding kinetics of Np and the kinetics of Rp folding to Np at 25 °C, it was found that Np is kinetically trapped by an unfolding barrier of 25.5 kcal/mol, and yet once unfolded, is prevented from folding by a comparable folding barrier. The folding mechanism of PMII is similar to that reported for pepsin. It is hypothesized that the PMII zymogen also utilizes a prosegment-catalyzed folding mechanism.
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functional chimera of porcine pepsin prosegment and plasmodium falciparum Plasmepsin II
Protein Engineering Design & Selection, 2010Co-Authors: Charity L Parrvasquez, Rickey Y YadaAbstract:: ProPlasmepsin II (zPMII) represents a unique member of the aspartic proteinase family, with a prosegment-enzyme interaction that is thus far unique among the pepsin-like proteases. The role of the prosegment in aspartic proteinase structure and function was investigated by generating two chimeric proteins, one with the pepsinogen prosegment fused to the mature region of PMII (pepproPMII) and a second with the prosegment of PMII fused to pepsin (PMIIpropep). Both chimeras were expressed using Escherichia coli; however, PMIIpropep was extremely unstable suggesting protein misfolding. Alternatively, pepproPMII was capable of both autoactivation and hydrolysis of a synthetic substrate. Similarly, when the PMII enzyme was expressed without a prosegment, it too exhibited activity against the synthetic enzyme. CD measurements indicated that pepproPMII had reduced thermal stability when compared with zPMII. This reduction of temperature stability may have resulted from the inability of the pepsinogen prosegment to stabilize the C-terminal domain of the PMII enzyme. The ability of PMII to fold in the presence of a completely non-homologous prosegment and in its absence suggests that prosegment is not critical to obtaining a functional enzyme in all pepsin-like enzymes but likely plays a role in protein stabilization.
Christoph Boss - One of the best experts on this subject based on the ideXlab platform.
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Inhibitors of aspartic proteases – potential antimalarial agents
Expert Opinion on Therapeutic Patents, 2006Co-Authors: Christoph Boss, Olivier Corminboeuf, Corinna Grisostomi, T WellerAbstract:This review emphasises the importance of research in the field of new antimalarial therapeutic agents, summarises the biology of Plasmepsin II, a protozoal aspartic protease, and other related Plasmepsins, and analyses the scientific literature and the patent literature describing efforts in the search for inhibitors of Plasmepsins. As there are only very limited efforts in this area by the pharmaceutical industry, the patent literature reviewed covers the period of the last 10 years and, in addition, the article discusses results published by academic research groups. Several approaches are based on earlier work in the field of HIV-1 protease inhibitors and of renin inhibitors.
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x ray structure of Plasmepsin II complexed with a potent achiral inhibitor
Journal of Biological Chemistry, 2005Co-Authors: Lars Prade, Christoph Boss, Sylvia Richardbildstein, Solange Meyer, Andrew Jones, Christoph BinkertAbstract:The malaria parasite Plasmodium falciparum degrades host cell hemoglobin inside an acidic food vacuole during the blood stage of the infectious cycle. A number of aspartic proteinases called Plasmepsins (PMs) have been identified to play important roles in this degradation process and therefore generated significant interest as new antimalarial targets. Several x-ray structures of PMII have been described previously, but thus far, structure-guided drug design has been hampered by the fact that only inhibitors comprising a statine moiety or derivatives thereof have been published. Our drug discovery efforts to find innovative, cheap, and easily synthesized inhibitors against aspartic proteinases yielded some highly potent non-peptidic achiral inhibitors. A highly resolved (1.6 A) x-ray structure of PMII is presented, featuring a potent achiral inhibitor in an unprecedented orientation, contacting the catalytic aspartates indirectly via the "catalytic" water. Major side chain rearrangements in the active site occur, which open up a new pocket and allow a new binding mode of the inhibitor. Moreover, a second inhibitor molecule could be located unambiguously in the active site of PMII. These newly obtained structural insights will further guide our attempts to improve compound properties eventually leading to the identification of molecules suitable as antimalarial drugs.
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inhibitors of Plasmepsin II potential antimalarial agents
Chimia, 2004Co-Authors: Christoph Boss, Sylvia Richardbildstein, Rocco Furnari, Jeanmarc Bourgeois, Olivier Corminboeuf, Corinna Grisostomi, Lionel Coppex, Luke Harris, Lars Prade, Solange MeyerAbstract:Malaria is a very serious infectious disease affecting over two billion people worldwide. Currently available antimalarial drugs are losing effectiveness due to the emergence and the spread of resistant parasite strains. In order to regain control over the disease, new treatments are urgently needed. Drug discovery efforts in this direction are most likely to be successful if they target a novel mechanism of action. Such approaches will lead to antimalarial medicines that are functionally and structurally different from the existing drugs and therefore will have the potential to overcome existing resistances. Our own efforts are focused on the aspartic protease Plasmepsin II (PMII) which is a promising new drug target for future antimalarial therapies. We have found structurally simple, moderately active, non-peptide inhibitors of Plasmepsin II which offer ample opportunity for further optimization efforts.
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synthesis of Plasmepsin II inhibitors potential antimalarial agents
Molecules, 2003Co-Authors: Reto Mueller, Marianne Huerzeler, Christoph BossAbstract:A new series of Plasmepsin II (PM II) inhibitors has been prepared based on 4-aminopiperidine-tert-butyl-carbamate (1). These compounds might be useful as antimalarial drugs acting via a new mechanism, and therefore be less susceptible to parasite resistance now often observed with current antimalarial therapies. Some of the final compounds prepared exhibited encouraging inhibitory activity towards PM II.
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Synthesis of Plasmepsin II Inhibitors – Potential Antimalarial Agents
Molecules, 2003Co-Authors: Reto Mueller, Marianne Huerzeler, Christoph BossAbstract:A new series of Plasmepsin II (PM II) inhibitors has been prepared based on 4-aminopiperidine-tert-butyl-carbamate (1). These compounds might be useful as antimalarial drugs acting via a new mechanism, and therefore be less susceptible to parasite resistance now often observed with current antimalarial therapies. Some of the final compounds prepared exhibited encouraging inhibitory activity towards PM II.
Christoph Binkert - One of the best experts on this subject based on the ideXlab platform.
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inhibitors of Plasmepsin II potential antimalarial agents
Bioorganic & Medicinal Chemistry Letters, 2006Co-Authors: Olivier Corminboeuf, Corinna Grisostomi, Lars Prade, Solange Meyer, Guillaume Dunet, Mehdi Hafsi, Julien Grimont, Christoph Binkert, Andrew Jones, Reto BrunAbstract:In order to overcome the problem of drug resistance in malaria, it appears wise to concentrate drug discovery efforts toward new structural classes and new mechanisms of action. We report our results, targeting Plasmepsin II, a Plasmodium falciparum aspartic protease active in hemoglobin degradation, a parasite specific catabolic pathway. The results show that the new structural class is not only inhibiting PMII in vitro but is also active in a P. falciparum infected human red blood cell assay.
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x ray structure of Plasmepsin II complexed with a potent achiral inhibitor
Journal of Biological Chemistry, 2005Co-Authors: Lars Prade, Christoph Boss, Sylvia Richardbildstein, Solange Meyer, Andrew Jones, Christoph BinkertAbstract:The malaria parasite Plasmodium falciparum degrades host cell hemoglobin inside an acidic food vacuole during the blood stage of the infectious cycle. A number of aspartic proteinases called Plasmepsins (PMs) have been identified to play important roles in this degradation process and therefore generated significant interest as new antimalarial targets. Several x-ray structures of PMII have been described previously, but thus far, structure-guided drug design has been hampered by the fact that only inhibitors comprising a statine moiety or derivatives thereof have been published. Our drug discovery efforts to find innovative, cheap, and easily synthesized inhibitors against aspartic proteinases yielded some highly potent non-peptidic achiral inhibitors. A highly resolved (1.6 A) x-ray structure of PMII is presented, featuring a potent achiral inhibitor in an unprecedented orientation, contacting the catalytic aspartates indirectly via the "catalytic" water. Major side chain rearrangements in the active site occur, which open up a new pocket and allow a new binding mode of the inhibitor. Moreover, a second inhibitor molecule could be located unambiguously in the active site of PMII. These newly obtained structural insights will further guide our attempts to improve compound properties eventually leading to the identification of molecules suitable as antimalarial drugs.
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development of a new class of inhibitors for the malarial aspartic protease Plasmepsin II based on a central 7 azabicyclo 2 2 1 heptane scaffold
Helvetica Chimica Acta, 2003Co-Authors: David A Carcache, Francois Diederich, Simone R Hortner, Paul Seiler, Arnulf Dorn, Hans Peter Marki, Christoph BinkertAbstract:Plasmepsin II (PMII), a malarial aspartic protease involved in the catabolism of hemoglobin in parasites of the genus Plasmodium, and renin, a human aspartic protease, share 35% sequence identity in their mature chains. Structures of 4-arylpiperidine inhibitors complexed to human renin were reported by Roche recently. The major conformational changes, compared to a structure of renin, with a peptidomimetic inhibitor were identified and subsequently modeled in a structure of PMII (Fig. 1). This distorted structure of PMII served as active-site model for a novel class of PMII inhibitors, according to a structure-based de novo design approach (Fig. 2). These newly designed inhibitors feature a rigid 7-azabicyclo[2.2.1]heptane scaffold, which, in its protonated form, is assumed to undergo ionic H-bonding with the two catalytic Asp residues at the active site of PMII. Two substituents depart from the scaffold for occupancy of either the S1/S3 or S2′-pocket and the hydrophobic flap pocket, newly created by the conformational changes in PMII. The inhibitors synthesized starting from N-Boc-protected 7-azabicyclo[2.2.1]hept-2-ene (6; Schemes 1–5) displayed up to single-digit micromolar activity (IC50 values) toward PMII and good selectivity towards renin. The clear structureactivity relationship (SAR; Table) provides strong validation of the proposed conformational changes in PMII and the occupancy of the resulting hydrophobic flap pocket by our new inhibitors.
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a new class of inhibitors for the malarial aspartic protease Plasmepsin II based on a central 11 azatricyclo 6 2 1 02 7 undeca 2 4 6 triene scaffold
Helvetica Chimica Acta, 2003Co-Authors: David A Carcache, Francois Diederich, Simone R Hortner, Arnulf Dorn, Hans Peter Marki, Andreas Bertogg, Christoph BinkertAbstract:A new class of nonpeptidic inhibitors of the malarial aspartic protease Plasmepsin II (PMII) with up to single-digit micromolar activities (IC50 values) was developed by structure-based de novo design. The active-site matrix used in the design was based on an X-ray crystal structure of PMII, onto which the major conformational changes seen in the structure of renin upon complexation of 4-arylpiperidines-including the unlocking of a new hydrophobic (flap) pocket - were modeled. The sequence identity of 35% between mature renin and PMII had prompted us to hypothesize that an induced-fit adaptation around the active site as observed in renin might also be effective in PMII. The new inhibitors contain a central 11-azatricyclo[6.2.1.0(2.7)]undeca-2(7),3,5-triene core, which, in protonated form, undergoes ionic H-bonding with the two catalytic Asp residues at the active site of PMII (Figs. 1 and 2). This tricyclic scaffold is readily prepared by a Diels-Alder reaction between an activated pyrrole and a benzyne species generated in situ (Scheme 1). Two substituents with naphthyl or 1,3-benzothiazole moieties are attached to the central core (Schemes 1-4) for accommodation in the hydrophobic flap and S1/S3 (or S2', depending on the optical antipode of the inhibitor) pockets at the active site of the enzyme. The most-potent inhibitors (+/-)-19a -19c (IC50 3-5 mum) and (+/-)-23b (2 mum) ( Table) bear an additional Cl-atom on the 1,3-benzothiazole moiety to fully fill the rear of the flap pocket. Optimization of the linker between the tricyclic scaffold and the 1,3-benzothiazole moiety, based on detailed conformational analysis (Figs. 3 and 4), led to a further small increase in inhibitory strength. The new compounds were also tested against other aspartic proteases. They were found to be quite selective against renin, while the selectivity against cathepsin D and E, two other human aspartic proteases, is rather poor (Table). The detailed SARs established in this investigation provide a valuable basis for the design of the next generations of more-potent and -selective PMII inhibitors with potential application in a new antimalarial therapy.
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inhibitors of the plasmodium falciparum parasite aspartic protease Plasmepsin II as potential antimalarial agents
Current Medicinal Chemistry, 2003Co-Authors: Christoph Boss, Sylvia Richardbildstein, Solange Meyer, T Weller, W Fischli, Christoph BinkertAbstract:Malaria is a very serious infectious disease against which the currently available drugs are loosing effectiveness. The main problem is the emergence and the spreading of resistant parasite strains. New treatments are needed in order to regain control over the disease. Drug discovery efforts towards this goal are likely to be more successful, if they focus towards novel mechanisms of action. Such efforts will result in drugs that are functionally and structurally different from the existing drugs and therefore will overcome existing resistances. Here we focus on the aspartic protease Plasmepsin II, which is a promising new drug target. We review the drug discovery efforts that were published in the literature on this enzyme, and we present the compounds synthesized at Actelion Pharmaceuticals Ltd.
Ilya Y Gluzman - One of the best experts on this subject based on the ideXlab platform.
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trafficking of Plasmepsin II to the food vacuole of the malaria parasite plasmodium falciparum
Journal of Cell Biology, 2004Co-Authors: Michael Klemba, Ilya Y Gluzman, Wandy L Beatty, Daniel E. GoldbergAbstract:fA amily of aspartic proteases, the Plasmepsins (PMs), plays a key role in the degradation of hemoglobin in the Plasmodium falciparum food vacuole. To study the trafficking of proPM II, we have modified the chromosomal PM II gene in P. falciparum to encode a proPM II–GFP chimera. By taking advantage of green fluorescent protein fluorescence in live parasites, the ultrastructural resolution of immunoelectron microscopy, and inhibitors of trafficking and PM maturation, we have investigated the biosynthetic path leading to mature PM II in the food vacuole. Our data support a model whereby proPM II is transported through the secretory system to cytostomal vacuoles and then is carried along with its substrate hemoglobin to the food vacuole where it is proteolytically processed to mature PM II.
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Naturally-occurring and recombinant forms of the aspartic proteinases Plasmepsins I and II from the human malaria parasite Plasmodium falciparum
FEBS Letters, 1999Co-Authors: Lorraine Tyas, Daniel E. Goldberg, Jennifer Westling, Ilya Y Gluzman, Richard P. Moon, Katharina Rupp, Robert G. Ridley, Colin BerryAbstract:Comparable kinetic parameters were derived for the hydrolysis of peptide substrates and the interaction of synthetic inhibitors with recombinant and naturally-occurring forms of Plasmepsin II. In contrast, recombinant Plasmepsin I was extended by 12 residues at its N-terminus relative to its naturally-occurring counterpart and a 3–10-fold diminution in the kent values was measured for substrate hydrolysis by the recombinant protein. However, comparable K1 values were derived for the interaction of two distinct inhibitors with both forms of piasmepsin I, thereby validating the use of recombinant material for drug screening. The value of Plasmepsin I inhibitors was determined by assessing their selectivity using human aspartic proteinases.
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evaluation of a structure based statine cyclic diamino amide encoded combinatorial library against Plasmepsin II and cathepsin d
Bioorganic & Medicinal Chemistry Letters, 1998Co-Authors: Carolyn Diianni Carroll, Daniel E. Goldberg, Ilya Y Gluzman, Theodore O Johnson, Marc Orlowski, Giorgio Lauri, Roland E DolleAbstract:Abstract A structure-based 18,900-member combinatorial library was synthesized containing a statine template and three cyclic diamino acids as potential P 1 ′, P 2 –P 4 surrogates. Evaluation of this encoded library against two aspartyl proteases, Plasmepsin II and cathepsin D, led to the identification of selective inhibitors for each enzyme.
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identification of potent inhibitors of plasmodium falciparum Plasmepsin II from an encoded statine combinatorial library
Bioorganic & Medicinal Chemistry Letters, 1998Co-Authors: Carolyn Diianni Carroll, Ilya Y Gluzman, Hitesh K Patel, Theodore O Johnson, Marc Orlowski, Zhenmin He, Cullen L Cavallaro, Anna Oksman, James A Connelly, Daniel ChelskyAbstract:An encoded 13,020-member combinatorial library was synthesized containing a statine core. Evaluation of this library with Plasmepsin II, an aspartyl protease required for hemoglobin metabolism in the malaria parasite, led to the identification of potent and selective inhibitors as well as novel structure-activity relationships.
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structure and inhibition of Plasmepsin II a hemoglobin degrading enzyme from plasmodium falciparum
Proceedings of the National Academy of Sciences of the United States of America, 1996Co-Authors: Abelardo M Silva, S V Gulnik, P Maier, Jack R Collins, T N Bhat, P J Collins, Raul E Cachau, Kathryn E Luker, Ilya Y Gluzman, Susan E FrancisAbstract:Plasmodium falciparum is the major causative agent of malaria, a disease of worldwide importance. Resistance to current drugs such as chloroquine and mefloquine is spreading at an alarming rate, and our antimalarial armamentarium is almost depleted. The malarial parasite encodes two homologous aspartic proteases, Plasmepsins I and II, which are essential components of its hemoglobin-degradation pathway and are novel targets for antimalarial drug development. We have determined the crystal structure of recombinant Plasmepsin II complexed with pepstatin A. This represents the first reported crystal structure of a protein from P. falciparum. The crystals contain molecules in two different conformations, revealing a remarkable degree of interdomain flexibility of the enzyme. The structure was used to design a series of selective low molecular weight compounds that inhibit both Plasmepsin II and the growth of P. falciparum in culture.