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Use of a cysteine protease of plasmodium vivax

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Title: Use of a cysteine protease of plasmodium vivax.
Abstract: A use of vivapain-4 (VX-4), which is a cysteine protease of Plasmodium vivax, showing pH-dependent switching of substrate specificity, is provided. More specifically, a method of treating a parasitic disease caused by Plasmodium vivax by inhibiting VX-4; a method of screening a protease inhibitor acting on VX-4, wherein the protease inhibitor is useful as an anti-malarial agent acting on Plasmodium species, for example, Plasmodium vivax; and a method of identifying the activity of VX-4, are provided. ...


Browse recent LexyoumeIPGroup, PLLC patents - Chantilly, VA, US
Inventors: YOON KONG, BYOUNG-KUK NA, SEON-HEE KIM, YOUNG-AN BAE
USPTO Applicaton #: #20110046044 - Class: 514 44 (USPTO) - 02/24/11 - Class 514 


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The Patent Description & Claims data below is from USPTO Patent Application 20110046044, Use of a cysteine protease of plasmodium vivax.

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This application claims the benefit of U.S. Provisional Application No. 61/236,198, filed Aug. 24, 2009, which is incorporated by reference herein in its entirety for any purpose.

BACKGROUND OF THE INVENTION

The present invention relates to vivapain-4 (VX-4), which is a cysteine protease of Plasmodium vivax, showing pH-dependent switching of substrate specificity. More specifically, the present invention relates to a method of treating a parasitic disease caused by Plasmodium vivax by inhibiting VX-4, a method of screening a protease inhibitor acting on VX-4, wherein the protease inhibitor is useful as an anti-malarial agent acting on Plasmodium species, for example, Plasmodium vivax, and a method of identifying the activity of VX-4.

DESCRIPTION OF RELATED ART

Plasmodium vivax, one of the most predominant human malarial species worldwide, causes hundreds of millions of illnesses each year, and can result in severe morbidity and mortality. Emergence and spread of multidrug resistant vivax malaria is an increasing problem, and is associated with fatal disease, especially in children.

Cysteine proteases of malaria parasites are intimately involved in a variety of physiological processes essential for the parasite\'s survival. The potential biological significance of the cysteine proteases of P. falciparum such as falcipain-2 (FP-2), -2B (-2′) and -3 in conversion of precursor molecules into mature active proteins and erythrocytic rupture via cleavage of cytoskeletal proteins followed by merozoite release has been well characterized. Their independent roles in hemoglobin digestion in the food vacuole and coordinated function with other proteases in regulation of hemoglobin hydrolysis have been elucidated. These three FP-encoding genes cluster on chromosome 11 within a narrow 12-kb stretch, called the cysteine protease island. Another papain-like cysteine protease, FP-1, is located on chromosome 14. It is expressed in the asexual stage and is involved in oocyst production in mosquitoes and in the early invasive merozoite stage.

Two cysteine proteases, vivapain-2 (VX-2) and vivapain-3 (VX-3), have been identified in P. vivax. The VX-2 and VX-3 genes are located on chromosome 9, and the proteins share a number of biophysical and biochemical features with FP-2 and FP-3, including a long prodomain with a predicted short N-terminal extension, acidic pH optima, and requirement for reducing conditions for maximal enzyme activity. Structural analysis of VX-2 and VX-3 proteins has revealed a topology similar to those of FP-2 and -3; however, some critical differences exist between the sizes of the binding pockets and amino acid (AA) binding preferences, which include the preference for positively charged residues at P1 and Leu at P2 position. A gene (XM—001612308) showing a significant similarity to FP-1 has recently become available in the nucleotide sequence of P. vivax chromosome 12 in the GenBank database (PVX—195290, PVX—240290 and PVX—239290), while its biochemical properties and biological activity remain unclear.

Interests in specific inhibitors impeding the cysteine protease functions of P. falciparum and P. vivax have focused on their chemotherapeutic applicability, which might impair normal parasite growth in vitro. For example, rupture of the erythrocyte membrane by the invasive parasite is inhibited by broad-spectrum inhibitors of serine and cysteine proteases. Identification and further characterization of P. vivax cysteine proteases is essential not only to investigate their biological roles but also to characterize targets for antimalarial drugs. However, comprehensive studies of P. vivax cysteine proteases have been highly hindered mainly due to the inability to culture P. vivax.

SUMMARY

OF THE INVENTION

One embodiment provides a method of treating a parasitic disease caused by Plasmodium vivax, by administering an inhibitor against Plasmodium vivax cysteine protease (VX-4, AAT91956, SEQ ID NO: 1) to a patient in need of the parasitic disease treatment, wherein the inhibitor is capable of inhibiting the expression of glutamic acid at 180th position (Glu180) in VX-4, or substituting the Glu180 with an amino acid other than glutamate, or inactivating the Glu180, wherein the number of the amino acid position is initiated from the mature domain (SEQ ID NO: 2) of VX-4.

Another embodiment provides a method of screening an inhibitor against VX-4 or an anti-malarial agent against Plasmodium vivax using glutamic acid at 180th position (Glu180) in VX-4 as a target.

Another embodiment provides a method of screening an inhibitor against VX-4 or an anti-malarial agent against Plasmodium vivax using a pH-dependent substrate specificity of VX-4.

Still another embodiment provides a method of identifying the activity of VX-4 by examining a pH-dependent substrate specificity of VX-4.

These and other embodiments of the invention will be more fully understood from the following description of the invention and the claims appended hereto.

DETAILED DESCRIPTION

OF THE EMBODIMENT

The inventors isolated and identified a novel cysteine protease of P. vivax, designated as vivapain-4 (VX-4, AAT91956, SEQ ID NO: 1), which displays highly unusual pH-dependent substrate specificity, and characterized the biochemical properties of VX-4. Molecular modeling and subsequent mutation analysis of VX-4 demonstrated that Glu180 is involved in the pH-dependent substrate specificity of VX-4. The protease is localized in the cytoplasm of the whole erythrocytic stages of the parasite. It effectively hydrolyzes actin at neutral pH (e.g., pH 6.8 to 7.2, preferably approximately pH 7) and plasmepsin 4 at neutral and acidic pHs (e.g., pH 5-7), supporting its role in the maintenance of cellular homeostasis and architectural remodeling of the parasite during development.

Plasmodium vivax affects hundreds of millions each year and results in severe morbidity and mortality. Plasmodial cysteine proteases (CPs) play crucial roles during the progression of malaria since inhibition of these molecules impairs parasite growth. These CPs might targeted for new antimalarial drugs. The inventors herein characterized a novel P. vivax CP (VX-4), which appeared to evolve differentially among primate Plasmodium species. VX-4 showed highly unique substrate preference depending on surrounding micro-environmental pH. It effectively hydrolyzed benzyloxycarbonyl-Leu-Arg-4-methyl-coumaryl-7-amide (Z-Leu-Arg-MCA) and Z-Phe-Arg-MCA at acidic pH and Z-Arg-Arg-MCA at neutral pH. Three amino acids (Ala90, Gly157 and Glu180) that delineate the S2 pocket were found to be substituted in VX-4. Hereinafter, the amino acid positions of Ala90, Gly157 and Glu180 are numbered from the mature domain of VX-4, and the mature domain (SEQ ID NO: 1) of VX-4 and the initial peptide thereof are shown in FIGS. 1A and 1B. Alteration of Glu180 abolished activity against Z-Arg-Arg-MCA at neutral pH, indicating the importance of Glu180 in the pH-dependent substrate preference. VX-4 hydrolyzed actin at neutral pH and hemoglobin at acidic pH, and participated in plasmepsin IV activation at neutral/acidic pH. VX-4 was localized in the food vacuoles and cytoplasm of the erythrocytic stage of P. vivax. The differential substrate preferences depending on pH suggested a highly efficient mechanism to enlarge biological implications of VX-4, including hemoglobin degradation, maturation of plasmepsin, and remodeling of the parasite architecture during growth and development of P. vivax.

Based on the above study, the present invention was completed. The present invention will be described in detail as below.

Definitions

For convenience, certain terms employed in the specification, examples, and appended claims are collected here.

It is to be understood that this invention is not limited to the particular methodology, protocols, animal species or genera, and reagents described, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention that will be limited only by the appended claims.

Therefore, the term “a patient in need of treatment” as used herein will refer to any subject or patient who currently has or may develop any of parasitic diseases caused by P. vivax.

The term “treating” or “treatment” as used herein, refers to any indicia of success in the prevention or amelioration of pathology or condition of the parasitic diseases caused by P. vivax, or making the pathology or condition more tolerable to the patient, or improving a subject\'s physical or mental well-being. In some instances, treatment with the agent of the present invention will be done in combination with other agent to prevent, inhibit, or arrest the progression of the parasitic diseases.

The term “therapeutic effect” as used herein, refers to the effective improvement in or reduction of symptoms of parasitic diseases. The term “a therapeutically effective amount” as used herein means a sufficient amount of one or more of the compounds of the invention to produce a therapeutic effect, as defined above, in a subject or patient in need of such parasitic disease treatment.

The terms “subject” or “patient” are used herein interchangeably and as used herein mean any mammal including but not limited to human beings including a human patient or subject to which the compositions of the invention can be administered. The term mammals include human patients, both male and female and non-human primates, as well as experimental animals such as rodent (e.g., rabbits, rats, mice, and the like) and other animals.

The term “degrading activity” includes all enzymatic activity of cysteine protease, such as a hydrolytic activity, cleavage activity, and the like.



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stats Patent Info
Application #
US 20110046044 A1
Publish Date
02/24/2011
Document #
File Date
04/24/2014
USPTO Class
Other USPTO Classes
International Class
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Drawings
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Cysteine
Parasitic Disease
Plasmodium
Protease Inhibitor


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