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Compositions and methods for treating malaria with cupredoxin and cytochrome

Inactive Publication Date: 2008-07-16
THE BOARD OF TRUSTEES OF THE UNIV OF ILLINOIS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Although some drugs such as chloroquine, which targets the heme detoxification pathway, are used to treat malaria, there is an increased incidence of parasite resistance to the drug and mosquito vector resistance to the insecticide

Method used

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  • Compositions and methods for treating malaria with cupredoxin and cytochrome
  • Compositions and methods for treating malaria with cupredoxin and cytochrome
  • Compositions and methods for treating malaria with cupredoxin and cytochrome

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0220] Example 1: In vitro inhibition of Plasmodium falciparum parasitemia by cupredoxin and cytochromes

[0221] Cupredoxin bacterial wt azurin, M44KM64E azurin, ferrothiocyanin and cyanobacterial plastocyanin and cytochrome Pseudomonas aeruginosa cytochrome c 551 , human cytochrome c and S. laminatus cytochrome f were tested in a normal red blood cell (RBC) assay at a concentration of 200 μg / ml 30 hours after incubation. In these experiments, normal RBCs were washed twice with serum-free medium and resuspended to 10% hematocrit in complete RPMI. 200 μl of 10% Hct RBC was added to each well of 24 wells (final 2% Hct, 1 mL), in addition to 30 μl of complete RPMI containing 666 μM of recombinant cupredoxin or cytochrome protein at a final concentration of 200 μM. Schizont stage parasites were prepared by centrifuging late stage cultures through a Percoll pad at 3200 rpm for 10 minutes. For infection, a volume of 500 μl of 4 × 10 6 parasites / hole. Plates were incubated for 3...

Embodiment 2

[0224] Example 2: Inhibition of Intracellular Replication of Plasmodium falciparum by Ferrothiocyanin

[0225] To determine whether bacterial redox proteins were able to inhibit intracellular replication of Plasmodium, erythrocytes were loaded to an intracellular recombinant protein concentration of 200 μg / ml using hypotonic ghost preparations. Cells were then washed, resuspended, and infected with schizont-stage parasites (Plasmodium falciparum) as described in Example 1 . RBC ghosts were incubated for 19 and 40 hours to make Giemsa smears.

[0226] Compared to infection of normal erythrocytes in Example 1, only ferrothiocyanin reduced total parasitemia in loaded cell ghost cultures. At 19 hours, there were no significant differences in invasion and ring formation, with empty ghosts at 5.0±0.4% and ferrothiocyanin-loaded ghosts at 4.5±1.0%. However, at 40 hours, ferthiocyanin-loaded ghosts had lower levels of infection. No major effect was seen at 19 hours with any bacteri...

Embodiment 3

[0229] Example 3: Structural homology between azurin and the Fab fragment of the G17.12 monoclonal antibody complexed with PfMSP1-19

[0230] Previous studies have shown that cupredoxins display structural similarities to the variable regions of members of the immunoglobulin superfamily. (Gough & Chothia, Structure 12: 917-925 (2004); Stevens et al., J. Mol. Recognit. 18: 150-157 (2005)). The DALI algorithm (Holm & Park, Bioinformatics 16:566-567 (2000)) was used. Azurin (1JZG) from Pseudomonas aeruginosa was searched for structural similarity in 3D databases. Azurin exhibits structural similarity to the Fab fragment of the G17.12 mAb complexed with the Fab fragment of the G17.12 mAb of the PfMSP1-19 fragment of the MSP1 schizont surface protein of P. falciparum. (Pizarro et al., J. Mol. Biol. 328:1091-1103 (2003)). (Table 6) Azurin also exhibits structural similarity to ICAM-1 (Table 6), which is involved in cerebral malaria and may be involved in the sequestration of P. f...

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Abstract

The present invention relates to cupredoxin and cytochrome and their use, separately or together, to inhibit the spread of parasitemia in mammalian red blood cells and other tissues infected by the malaria parasite, and in particular the parasitemia of human red blood cells by P. falciparum. The invention provides isolated peptides that are variants, derivatives or structural equivalents of cupredoxins or cytochrome c, and compositions comprising cupredoxins and / or cytochrome c, or variants, derivatives or structural equivalents thereof, that are useful for treating or preventing malaria infection in mammals. Further, the invention provides methods to treat mammalian patients to prevent or inhibit the growth of malarial infection in mammals. The invention also provides methods to prevent the growth of malaria infection in insect vectors.

Description

[0001] related application [0002] This application claims U.S. Provisional Patent Application ______, entitled "Compositions and Methods for Treating HIV Infection with Cupredoxin and Cytochrome c," filed jointly on ______, U.S. Provisional Patent Application 60 / 780,868, filed March 10, 2006, May 2005 Priority to U.S. Provisional Patent Application 60 / 682,813, filed October 20, 11 / 244,105, filed October 6, 2005, and U.S. Provisional Patent Application 60 / 680,500, filed May 13, 2005, which 11 / 244,105 claims priority to U.S. Provisional Patent Application 60 / 616,782, filed October 7, 2004, and this application is a continuation-in-part of U.S. Patent Application 10 / 720,603, filed November 11, 2003, which U.S. Patent Application 10 / 720,603 claims priority to U.S. Provisional Patent Application 60 / 414,550, filed August 15, 2003 and is a continuation-in-part of U.S. Patent Application 10 / 047,710, filed November 15, 2002, which claims 2001 2 Priority to U.S. Provisional Patent App...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P21/04
CPCY02A50/30
Inventor A·查克拉巴蒂T·D·古普塔山田亨A·乔杜里A·菲亚略洪昌秀
Owner THE BOARD OF TRUSTEES OF THE UNIV OF ILLINOIS
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