WO2013035107A1 - Peptides thérapeutiques - Google Patents

Peptides thérapeutiques Download PDF

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Publication number
WO2013035107A1
WO2013035107A1 PCT/IN2012/000578 IN2012000578W WO2013035107A1 WO 2013035107 A1 WO2013035107 A1 WO 2013035107A1 IN 2012000578 W IN2012000578 W IN 2012000578W WO 2013035107 A1 WO2013035107 A1 WO 2013035107A1
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peptide
atpase
subunit
peptides
falciparum
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PCT/IN2012/000578
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English (en)
Inventor
Grish Chandra Varshney
Kaliannan Ganesan
Ashu SHAH
Shailendra Kumar GAUTAM
Rakesh Bhatia
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Council Of Scientific And Industrial Research
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Publication of WO2013035107A1 publication Critical patent/WO2013035107A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to cysteine constrained cyclic peptide against recombinant subunit B of P falciparum V-H + ATPase. These peptides inhibit P falciparum growth in vitro and can be exploited for their therapeutic values in malaria and also in other diseases such as osteoporosis and cancer where V-H + ATPase over expression is a characteristics of diseased cells.
  • the invention relates to a peptide mediated therapy of diseases caused by pathogens having similar B subunit of V-H + ATPase.
  • V-rf 1" ATPase has been implicated in the maintenance of the intracellular pH (pHi) of infected erythrocyte (Hayashi et al., 2000), and also in energizing the secondary transport of diverse solutes (Moriyama et al., 2003).
  • Phage display technology has been used in cancer not only for the identification of targets but also in the development of peptide based drugs (Ladner et al., 2004) and vaccines (Wang et al., 2004).
  • high-affinity ligands for protein targets could be selected from phage display peptide libraries (Cwirla et al., 1990).
  • screening of peptides from phage display technique was done to inhibit the function of Hspl 6.3 (Gupta et al 2009).
  • targeting with a peptide inhibitor may provide a useful reagent to assist small- molecule drug discovery (Arkin and Wells, 2004; DeLano et al., 2000).
  • phage display system In malaria, phage display system has been used to investigate host-pathogen interactions (Ghosh et al., 2001). 15-mer peptides specific to P. falciparum AMA 1 were selected by panning phage display library. These peptides were found effective in blocking erythrocyte invasion thereby leading to inhibition of P .falciparum growth in vitro (Li et al., 2002). In another study, the peptides that bound specifically to recombinant serine repeat antigen (SERA5) were studied for their effect on parasite growth.
  • SERA5 serine repeat antigen
  • the criteria for selecting a target protein in this study were: a) presence on infected red blood cell membrane, b) conserved nature in different species of Plasmodium and, c) its function. Presence of V-H+ ATPase protein in different species of Plasmodium with closer E-values and high identity revealed its significance in the parasite. Besides, it is the first functional enzyme reported on infected cell membrane (Marchesini et al, 2005).
  • V-H + ATPase has been targeted by different class of inhibitors.
  • a benzolactone based class of inhibitors e.g. Bafilomycin and concanamycin, are effective in blocking the proton extrusion from V-H + ATPase pump.
  • the structural mimics of these compound have been screened which effectively inhibit parasite growth specifically blocking subunit C of enzyme (Saliba et al., 2010). Further attempts to screen inhibitors against other subunits will provide a momentum for drug discovery.
  • Yet another object of the present invention is cloning, expression and purification of recombinant subunit B of V-H + ATPase of P. falciparum.
  • Still another object of the present invention is recognition of P.falciparum infected cells by peptide phages reactive to recombinant subunit B.
  • Yet another object of the present invention is inhibition of P. falciparum growth in vitro by peptides corresponding to phages.
  • the present invention provides 7-mer cyclic peptides useful in peptide mediated therapy of diseases caused by pathogens having similar B subunit V-H + ATPase
  • the peptide is a 7-mer cysteine constrained cyclic peptide.
  • the peptide targets the highly conserved B subunit of V- H+ ATPase
  • the peptide inhibit P. falciparum growth in vitro.
  • the peptide is useful for setting of screens to identify other potent therapeutic agents.
  • the peptide is selected for setting of screens to identify chemical analogues.
  • a pharmaceutical composition comprising a peptide for use as a therapeutic including pharmaceutically acceptable carrier.
  • the peptide is used for the treatment of Malaria caused by pathogen having similar B subunit of V-H + ATPase.
  • Figure 1 SDS-PAGE of recombinant subunit B of P. falciparum V-H + ATPase, purified by Ni-NTA affinity chromatography, followed by commossie staining. Molecular weight of purified protein is indicated with arrow.
  • FIG. 2 Localization of recombinant B subunit specific phage peptide binding sites in P.falciparum infected erythrocytes (IRBC) as revealed by immunofluorescence assay.
  • IRBC preincubated with selected phages (ATPase 10; row 1, ATPase 13; row 2 ), were coated on to the slide, treated with mouse anti- M13 antibody followed by goat anti-mouse IgG Alexa594 conjugate at 1 :600 dilution (Panel B). The parasite was counterstained with DAPI (Panel A).
  • Figure 3 In vitro parasite growth inhibition by recombinant B subunit specific peptides. EGTA was taken as a positive control.
  • the present invention relates to cysteine constrained cyclic peptide against recombinant subunit B of P falciparum V-H + ATPase. These peptides inhibit P falciparum growth in vitro and can be exploited for their therapeutic values in malaria and also in other diseases such as osteoporosis and cancer where V-H + ATPase over expression is a characteristics of diseased cells.
  • the invention relates to a peptide mediated therapy of diseases caused by pathogens having similar B subunit of V-H + ATPase.
  • the criteria for selecting a target protein were: 1) presence on infected erythrocyte membrane, 2) conserved nature in different species of Plasmodium and, 3) its function. Due to high complexity, only few infected cell surface molecules have been characterized. Most of these molecules such as PfEMP-1, rifins, stevors etc. are present on infected cell membrane with well known function but suffer from antigenic diversity/polymorphism or clonal antigenic variations (Hisaeda et al., 2004; Hisaeda et al., 2005) which cause great hinderance to target them. Accordingly, other proteins e.g.
  • Exp-2 (Export 2 protein), PIESP-1 , PIESP-2, V-H + ATPase present on infected cell membrane were selected for their sequence analysis by Blast homology available at www.ncbi.nlm.nih.gov. No conservation of Exp-2 and PIESP-2 was found in different species of plasmodium as indicated by differences in E-value, while PIESP-1 was relatively conserved but its function is still not known. On the other hand, presence of V-H+ ATPase protein in different species of Plasmodium ⁇ P. falciparum.
  • V- H + ATPase is present on NRBC membrane.
  • functional properties vary among various V-H + ATPase. Different cells and tissue specific isoforms of B subunit of V-H + ATPase make them a suitable drug target.
  • V-H + ATPase from different species of Plasmodium by using clustal X showed that this protein is conserved in human malaria parasite e.g. P. vivax, P.falciparum as well as in rodent parasite e.g. P. berghei, P. yoelii.
  • B subunit of V-H + ATPase (Seq Id no. 3) was selected as a target for peptide mediated therapy because of its accessibility on infected erythrocyte surface, conserved nature in different species and the functional importance of enzyme.
  • First and second PCR amplification was carried out using -200 ng template DNA in a final reaction volume of 50 ⁇ 1 containing 200 ⁇ of each dNTP, 200 nM of each primer ElFl (forward),ElRl (reverse) for 1 st fragment and E2Fl(forward),E2R2(reverse) for 2 nd fragment, IX PCR buffer and 2 units of enzyme (Barnes, 1994).
  • PCR amplifications were carried out for total of 35 cycles (denaturation: 95°C for 30 sec; annealing: 54°C for 30 sec in 1 st PCR and 47°C for 30 sec in 2 nd PCR; elongation: 72°C for 1.5 min depending on insert size to be amplified) followed by final extension cycle at 72°C for 10 min in an eppendorf thermal cycler.
  • Products of both PCR reactions were mixed and 50 ng of DNA was used as the template with ElFlas a forward primer and E2R2 as a reverse primer in third PCR amplification at the annealing temperature of 54° C.
  • the phage library used in the present invention Ph.D. TM-C7C Phage Display Peptide Library Kit, was purchased from New England BioLabs (Beverly, Mass.). This kits is based on a combinatorial library of random peptide 7 fused to a minor coat protein (pill) of Ml 3 phage. The displayed peptide is expressed at the N- terminus of pill, such that after the signal peptide is cleaved, the first residue of the coat protein is the first residue of the displayed peptide.
  • the Ph.D.TM-C7C library consist of approximately 2.8.times. l0.sup.9 and 2.7.times. l(hsup.9 sequences, respectively. A volume of 10 .mu.L contains about 55 copies of each peptide sequence. Each initial round of experiments was carried out using the original library provided by the manufacturer in order to avoid introducing any bias into the results.
  • 7-mer cysteine constrained phage display peptide library was used to first select the short cyclic peptides that bind to the recombinant B subunit (represented by SEQ ID NO: 3) of V-H + ATPase of P. falciparum and are able to recognize the infected cells. Briefly, the recombinant protein was coated onto the 96 well ELISA plate at pH 7.4, and incubated with lx lO 1 1 pfu of phage peptides for 2 hours at room temperature. The bound phage peptides were eluted under acidic conditions.
  • the plaques corresponding to protein bound phage peptides were randomly picked from 3rd pan titer plate, amplified in E.Coli ER2738 followed by their DNA isolation and then subjected to automated sequencing.
  • the selected phage peptides (Table 2) were checked for their binding with recombinant protein and infected RBC membrane by ELISA and immunofluorescence assay respectively.
  • Table 2 Panning of random 7 mer cysteine constrained phage display peptide library onto rec.B subunit of P.falciparum V-H 1" ATPase
  • Fig.2 presents a representative picture of immunofluorescence pattern as observed with ATPase 10 (Seq Id No. 1 ) and ATPase 13 (Seq Id No. 2) phages.
  • peptides screened for recombinant B subunit were found to localize on infected erythrocytes and therefore these peptides were assessed for their effect on parasite growth in culture. For this, hypoxanthine incorporation assa was done.
  • the P.falciparum (MRA102) culture was doubly synchronized by 5% sorbitol and suspended at 5% hematocrit and two different parasitemia of 2% and 5%. Then, the culture was incubated with different custom synthesized peptides at concentrations varying from 100 ⁇ g/ml to 1 mg/ml.
  • ATPaselO peptide showed 60% inhibition at 1000 ⁇ g/ml concentration (Fig.3). In contrast, peptides corresponding to ATPasel, ATPase3 and ATPase 5 did not have any effect.
  • the target protein, B subunit of V-H + ATPase is highly conserved functional molecule in different species of Plasmodium. Thus, malaria caused by different species can be treated by the set of drugs developed against this target.
  • the claimed peptides can be used as a potent inhibitor of B subunit restricting the malaria parasite growth in a dose dependent manner.
  • the peptide inhibitors can be targeted at multiple sites during malaria infection.
  • the claimed peptides can be used in other pathogen associated diseases where the selected peptides can be used against similar target as in malaria.
  • Phage ⁇ displayed peptides bind to the malarial protein apical membrane antigen ⁇ 1 and inhibit the merozoite invasion of host erythrocytes. J Biol Chem 277: 50303 D50310.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
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  • Engineering & Computer Science (AREA)
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  • Pharmacology & Pharmacy (AREA)
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Abstract

La présente invention concerne des peptides qui réagissent spécifiquement avec une sous-unité B de H+-ATPase vacuolaire de Plasmodium falciparum (ATPase V-H+). Les peptides ont été identifiés par adhérence sur plastique de banques peptidiques de présentation par phage avec une sous-unité B de ATPase V-H+ recombinée de P.falciparum. Les phages sélectionnés réagissent spécifiquement avec des cellules infectées par P.falciparum et les peptides libres correspondants inhibent la croissance des parasites in vitro. Les peptides identifiés peuvent être utilisés pour le traitement de la malaria et d'autres maladies provoquées par des pathogènes exprimant la sous-unité B d'ATPase V-H+.
PCT/IN2012/000578 2011-09-05 2012-09-04 Peptides thérapeutiques WO2013035107A1 (fr)

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IN2544DE2011 2011-09-05
IN2544/DEL/2011 2011-09-05

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10550172B2 (en) * 2015-03-20 2020-02-04 University Of Florida Research Foundation, Incorporated Serpin reactive center loop peptides and methods of use
WO2022193541A1 (fr) * 2021-03-19 2022-09-22 江苏元本生物科技有限公司 Polypeptide sur phage ciblant siglec-15

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10550172B2 (en) * 2015-03-20 2020-02-04 University Of Florida Research Foundation, Incorporated Serpin reactive center loop peptides and methods of use
WO2022193541A1 (fr) * 2021-03-19 2022-09-22 江苏元本生物科技有限公司 Polypeptide sur phage ciblant siglec-15

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