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User,
It's a small world in biophysical circles..evidently..
And you're the king of connectiondot..
Good stuff Bio..
All the best,
John
How big is phosphatidylserine?
How about European Commission big..
How about bring the biggest minds of "who's who" in "whosville" and call it the"flippase club"..
That's what the European Commision did..
It was called the "Project Virus Entry", and if you dig you'll find the "flipasse club".
http://www2.hu-berlin.de/virusentry/
Here's some of the flipasse members.
http://www2.hu-berlin.de/virusentry/members_research_organisations.htm
Now if you keep digging you'll find more interesting qualities..
Group of Molecular Biophysics
Chair: Prof. Andreas Herrmann
Address: Invalidenstraße 43, 10115 Berlin, Germany,
phone: 030-2093-8830, Fax: 030-2093-8585 (how to reach us)
http://www2.hu-berlin.de/biologie/molbp/
Now look what Doc Herrmann's been working on.. And how ironic I recently posted about VLP's (virus like particles)..
Nanomedicine. 2014 Jul;10(5):981-9. doi: 10.1016/j.nano.2014.02.008. Epub 2014 Mar 1.
aEnv-decorated phosphatidylserine liposomes trigger phagocytosis of HIV-virus-like particles in macrophages.
Gramatica A1, Petazzi RA2, Lehmann MJ3, Ziomkowska J1, Herrmann A1, Chiantia S4.
Author information
Abstract
Macrophages represent an important cellular target of HIV-1. Interestingly, they are also believed to play a potential role counteracting its infection. However, HIV-1 is known to impair macrophage immune functions such as antibody-mediated phagocytosis. Here, we present immunoliposomes that can bind HIV-1 virus-like particles (HIV-VLPs) while being specifically phagocytosed by macrophages, thus allowing the co-internalization of HIV-VLPs. These liposomes are decorated with anti-Env antibodies and contain phosphatidylserine (PS). PS mediates liposome internalization by macrophages via a mechanism not affected by HIV-1. Hence, PS-liposomes mimic apoptotic cells and are internalized into the macrophages due to specific recognition, carrying the previously bound HIV-VLPs. With a combination of flow cytometry, confocal live-cell imaging and electron microscopy we demonstrate that the PS-immunoliposomes presented here are able to elicit efficient HIV-VLPs phagocytosis by macrophages and might represent a new nanotechnological approach to enhance HIV-1 antigen presentation and reduce the ongoing inflammation processes.
FROM THE CLINICAL EDITOR:
This team of authors demonstrate that specific phosphatidylserin immunoliposomes are able to elicit efficient phagocytosis of HIV-virus-like particle by macrophages and might represent a new nanomedicine approach to enhance HIV-1 antigen presentation and reduce ongoing inflammation processes.
Copyright © 2014 Elsevier Inc. All rights reserved.
More confirmation please..
All the best,
John
There are hundreds of patents pounding away at phosphatidylserine's physiologic involvement.. I'm interested in PS receptors, such as TIM(1,2,3,4) and also TAM receptor family, and it appears the Department of French Health is too..
Title:
TIM RECEPTORS AS VIRUS ENTRY COFACTORS
Abstract:
The present invention concerns the use of an inhibitor of an interaction between phosphatidylserine and a TIM receptor for preventing or treating a virus entry cofactors, in particular phosphatidylserine harboring virus infection such as flavivirus infection.
CLAIMS
1 . An inhibitor of an interaction between phosphatidylserine and a TIM receptor for use for preventing or treating a virus infection, wherein said inhibitor is:
i TIM receptor inhibitor, and/or
a phosphatidylserine binding protein
2. An inhibitor for use according to claim 1 (i), wherein said TIM receptor is TIM-1 , TIM-3 or TIM-4.
3. An inhibitor for use according to claim 1 or 2, wherein said TIM receptor inhibitor is an anti-TIM receptor antibody, an antisense nucleic acid, a mimetic or a variant TIM receptor.
4. An inhibitor for use according to claim 1 or 2, wherein said phosphatidylserine binding protein is an anti-phosphatidylserine antibody or Annexin 5.
5. An inhibitor for use according to claim 3, wherein said TIM receptor inhibitor is a siRNA of sequence SEQ ID NO: 1 , 2, 3, or 4.
6. An inhibitor for use according to claim 1 , wherein said virus is a phosphatidylserine harboring virus.
7. An inhibitor for use according to any one of claims 1 to 6, wherein said phosphatidylserine harboring virus is an Alphavirus or a Flavivirus.
8. An inhibitor for use according to claim 7, wherein said Alphavirus is Chikungunya virus.
9. An inhibitor for use according to claim 7, wherein said Flavivirus is a West-Nile Virus, Yellow Fever Virus or Dengue Fever Virus.
10. An inhibitor for use according to any one of claims 1 to 9, wherein said inhibitor is for administration in combination with at least one other antiviral compound, either sequentially or simultaneously.
1 1 . An inhibitor for use according to claim 10, wherein said other antiviral compound is an inhibitor of an interaction of phosphatidylserine and a TAM receptor.
12. An inhibitor for use according to claim 1 1 , wherein said inhibitor of an interaction of phosphatidylserine and a TAM receptor is:
(i) a TAM receptor inhibitor, and/or
(ii) a Gas6 inhibitor.
13. An inhibitor for use according to any one of claims 1 to 12, wherein said inhibitor is formulated in a pharmaceutically acceptable composition.
14. A pharmaceutical composition comprising an inhibitor as defined in any one of claims 1 to 9 and additionally at least one other antiviral compound.
15. A pharmaceutical composition according to claim 14, wherein said at least one other antiviral compound is an inhibitor of an interaction of phosphatidylserine and a TAM receptor.
16. A pharmaceutical composition according to claim 15, wherein said inhibitor of an interaction of phosphatidylserine and a TAM receptor is:
(i) a TAM receptor inhibitor, and/or
(ii) a Gas6 inhibitor.
17. Use of an inhibitor as defined in any one of claims 1 to 9 in an in vitro method of inhibiting entry of a phosphatidylserine harboring virus in particular a flavivirus into a cell.
18. A method for preventing or treating a viral infection, in particular a PtdSer harboring virus infection such as a flavivirus infection, comprising administering to an individual in need thereof a therapeutically effective amount of an inhibitor of an interaction between phosphatidylserine and a TIM receptor.
Description:
TIM RECEPTORS AS VIRUS ENTRY COFACTORS
Field of the invention
The present invention concerns the use of an inhibitor of an interaction between phosphatidylserine and a TIM receptor for preventing or treating a viral infection.
Background to the invention
Viral infections are a major threat to public health. The emergence and expansion of life- threatening diseases caused by viruses (e.g. hemorrhagic fever and encephalitis), together with unmet conventional prevention approaches (e.g., vaccines) highlights the necessity of exploring new strategies that target these deadly pathogens.
The Flavivirus genus for example encompasses over 70 small-enveloped viruses containing a single positive-stranded RNA genome. Several members of this genus such as Dengue virus (DV), Yellow Fever Virus (YFV), and West Nile virus (WNV), are mosquito-borne human pathogens causing a variety of medically relevant human diseases including hemorrhagic fever and encephalitis (Gould and Solomon, 2008, Lancet, 371 :200-509; Gubler et a!., 2007, Fields Virology, 5th Edition, 1 153-1252). Dengue disease, which is caused by four antigenically related serotypes (DV1 to DV4), has emerged as a global health problem during the last decades and is one of the most medically relevant arboviral diseases. It is estimated that 50-100 million dengue cases occur annually and more than 2.5 billion people being at risk of infection. Infection by any of the four serotypes causes diseases, ranging from mild fever to life-threatening dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Despite the importance and increasing incidence of DV as a human pathogen, there is currently no licensed vaccine available against DV and the lack of anti-viral drugs severely restricts therapeutic options.
Future efforts to combat dengue disease require a better understanding of the DV life cycle. DV entry into target cells is a promising target for preventive as well as therapeutic anti-viral strategies since it is a major determinant of the host-range, cellular tropism and viral pathogenesis. During primary infection, DV enters host cells by clathrin- mediated endocytosis, a process driven by the interaction between the viral glycoprotein (E protein) with cellular receptors. Within the endosome, the acidic environment triggers an irreversible trimerization of the E protein that results in fusion of the viral and cell membranes, allowing the release of the viral capsid and genomic RNA into the cytosol. To date, the molecular bases of DV-host interactions leading to virus entry are poorly understood and little is known about the identity of the DV cellular receptor(s). DV is known to infect a wide range of cell types. DV may thus exploit different receptors, depending on the target cell, or use widely expressed entry molecules. Earlier studies indicated that DV virions make initial contact with the host by binding to heparan-sulfate proteoglycans on the cell membrane. These molecules recognize the positively charged residues on the surface of E protein and are thought to concentrate the virus at the target cell surface before its interactions with entry factors. Numerous cellular proteins such as heat shock protein 70 (HSP70), HSP90, GRP78/Bip, a lipopolysaccharide receptor-CD14 or the 37/67 kDa high affinity laminin have been proposed as putative DV entry receptors. However, their function in viral entry remains poorly characterized and of unclear physiological relevance. To date, the only well-characterized factors that actively participate in the DV entry program are DC-SIGN expressed on dendritic cells, L-SIGN expressed on liver sinusoidal endothelial cells and the mannose receptor (MR) expressed on macrophages. These molecules belong to the C-type lectin receptor family and bind mannose-rich N-linked glycans expressed on the DV E protein. However, DV infects cell types that do not express DC-SIGN, MR or L-SIGN, indicating that other relevant entry receptor(s) exist and remain to be identified.
Currently, DV has become a global problem and is endemic in more than 1 10 countries. Thus, development of a prophylactic or curative treatment DV infection is needed.
Moreover, deciphering the mechanism of DV internalization might also pave the way to developing treatment of other viral infections.
Description of the invention
The inventors have found that DV infection is mediated by the interaction between phosphatidylserine (PtdSer) present at the surface of the DV viral envelope and TIM receptor present at the surface of the host cell, and that such interaction can be blocked, thereby inhibiting entry of DV into host cells and preventing DV infection.
Furthermore, the inventors found that this interaction between phosphatidylserine (PtdSer) and TIM receptors is not only used by other flavivirus such as Yellow Fever Virus (YFN) and West Nile Virus (WNV) but also for example by the Chikungunya Virus showing that this interaction may represent a general mechanism exploited by viruses that incorporate phosphatidylserine (PtdSer) in their membrane.
Thus, the invention relates to an inhibitor of an interaction between phosphatidylserine and a TIM receptor for use for preventing or treating a viral infection, in particular a phosphatidylserine (PtdSer) harboring virus infection such as a flavivirus infection, wherein said inhibitor is preferably (i) a TIM receptor inhibitor, and/or (ii) a phosphatidylserine binding protein. Preferably, said interaction is a direct interaction.
By "a phosphatidylserine harboring virus infection" is meant in particular a "flavivirus infection". By "flavivirus infection" it is meant an infection with a Dengue virus (DV), a West Nile virus, a tick-borne encephalitis virus, a Saint-Louis encephalitis virus, a Japanese encephalitis virus or a yellow fever virus. Preferably, said TIM receptor is TIM-1 , TIM-3 or TIM-4. Preferably, said TIM receptor inhibitor is an anti-TIM receptor antibody, an antisense nucleic acid, a mimetic or a variant TIM receptor, and preferably said TIM receptor inhibitor is a siRNA. Preferably, said phosphatidylserine binding protein is an anti-phosphatidylserine antibody or Annexin 5.
Also provided is a pharmaceutical composition comprising an inhibitor of an interaction between phosphatidylserine and a TIM receptor and additionally at least one other antiviral compound. Preferably, said at least one other antiviral compound is an inhibitor of an interaction of phosphatidylserine and a TAM receptor.
Further provided is the use of an inhibitor of an interaction between phosphatidylserine and a TIM receptor in a method of inhibiting entry of a virus, in particular a PtdSer harboring virus such as a flavivirus, into a cell.
Also provided is a method for preventing or treating a viral infection, in particular a PtdSer harboring virus infection such as a flavivirus infection, comprising administering to an individual in need thereof a therapeutically effective amount of an inhibitor of an interaction between phosphatidylserine and a TIM receptor.
Also provided is the use of an inhibitor of an interaction between phosphatidylserine and a TIM receptor for the manufacture of a medicament for preventing or treating a viral infection, in particular a PtdSer harboring virus infection, in particular a flavivirus infection.
Definition
By "a phosphatidylserine harboring virus infection" is meant an infection with an enveloped virus that expresses or incorporates PtdSer in its membrane. Prior to infection, the PtdSer is exposed on the viral membrane to receptors of the host cell. Examples of enveloped viruses harboring PtdSer include, but are not limited to: Flavivirus (such as Dengue Virus, West Nile Virus, Yellow Fever Virus), Alphavirus (e.g. Chikungunya Virus), Filovirus (e.g. Ebola Virus), Poxivirus (e.g. Cowpox Virus) and Arenavirus (e.g. Lassa Virus).
"A phosphatidylserine harboring virus infection" may include, for example, a
"flavivirus infection". By "flavivirus infection" it is meant an infection with a Dengue virus (DV), a West Nile virus, a tick-borne encephalitis virus, a Saint-Louis encephalitis virus, a Japanese encephalitis virus or a yellow fever virus (Sabin et al., 1952, A.B. Am. J. Trop. Med. Hyg. 1 :30-50; Hammon et al., 1960, Trans. Assoc. Am. Physicians 73:140-155; Smithburn, 1940, Am. J. Trop. Med., 20:471 -492; Monath and Heinz, 1996, Flaviviruses, Fields Virology, 3rd edition, p.961 -1034; Gould and Solomon, 2008, Lancet, 371 :500-509). The Dengue virus may be of any serotype, i.e. serotype 1 , 2, 3 or 4.
By "interaction between phosphatidylserine and a TIM receptor" is meant the direct interaction between phosphatidylserine present at the surface of the PtdSer harboring virus and a TIM receptor present at the surface of the host cell. In fact, the inventors have found that the direct interaction between phosphatidylserine and TIM receptor permits the PtdSer-harboring virus infection or entry into the host cells.
By "inhibitor" is meant an agent that is able to reduce or to abolish the interaction between phosphatidylserine and a TIM receptor. Said inhibitor may also be able to reduce or abolish the expression of a TIM receptor. According to the invention, said inhibitor is (i) a TIM receptor inhibitor and/or (iii) a phosphatidylserine binding protein.
Preferably, said inhibitor is able to reduce or to abolish the interaction between phosphatidylserine and a TIM receptor, by at least 10, 20, 30, 40 %, more preferably by at least 50, 60, 70 %, and most preferably by at least 75, 80, 85, 90, 95, 96, 97, 98, 99, or 100%.
http://www.freepatentsonline.com/WO2013124327A1.html
Application Number:
EP2013/053391
Publication Date:
08/29/2013
Filing Date:
02/20/2013
Export Citation:
Click for automatic bibliography generation
Assignee:
INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE (INSERM) (101 Rue de Tolbiac, Paris, Paris, F-75013, FR)
International Classes:
C07K14/47; C07K14/705; C07K16/18; C07K16/28; C12N15/113; A61P31/14
Microvesicles, exosomes Wookie. This is what the therapy is targeting.
Not the tumor cell directly.
Remember tumor cells shed these microparticles, which BTW does include PS, IMO.
Anti PS is brilliant and the target, but who has the better mouse trap and best way to skin the cat?
More antips validation, in a roundabout way, IMO
All the best,
John
Bavituximab, and radiology:
If anyone's interested in knowing if Bavituximab can be radio "loaded"..
A click-chemistry based strategy for labeling an anti-phosphatidylserine (PS) antibody with copper-64 via a cross-bridged tetraazamacrocyclic chelator scaffold
J Nucl Med. 2014; 55 (Supplement 1):1185
Amit Kumar1, Guiyang Hao1, Li Liu1 and Xiankai Sun1
1 Radiology, The University of Texas Southwestern Medical Center, Dallas, TX
Abstract No. 1185
Objectives: Cross-bridged tetraazamacrocyclic chelator (CBTE2A) scaffold forms a kinetically inert copper complex with high in vivo stability, and is regarded as one of the "gold standard’’. Unfortunately, due harsh labeling conditions it is not under utilized for antibody labeling. In this work we demonstrate a unique method for antibody labeling under ambient conditions utilizing CBTE2A scaffold. The method involves prelabeling CBTE2A based scaffold (CBTE1A) with 64Cu and its subsequent reaction with antibody via tertrazine-norbornene mediated click reaction. We demonstrate the effectiveness of this technique by labeling and imaging bavituximab, a chimeric monoclonal antibody designed for the treatment of cancers, with 64Cu.
Methods: Norbornene moiety was attached to the free acid group of the tert butyl protected CBTE1A scaffold via carbodiimide chemistry. The compound was then deprotected and labeled with 64Cu in ammonium acetate buffer. Tetrazine moiety was attached to bavituximab via carbodiimide chemistry and the mixture purified by FPLC. Copper-64 labeled CBTE1A was subsequently mixed with tetrazine modified bavituximab in phosphate buffer and the mixture analyzed with radio FPLC. The resultant mixture was purified and in vivo imaging was performed on LNCaP tumor bearing mice.
Results: The 64Cu-labeled CBTE1A was obtained in 90% radio labeling yield and greater than 99% purity. The radio FPLC analysis of the reaction mixture showed a strong radio peak for bavituximab. In vivo imaging showed uptake and retention of labeled bavituximab at 48 h post injection.
Conclusions: We have successfully demonstrated a method to radiolabel antibodies under ambient condition using CBTE2A based scaffold. The in vivo results suggest the antibody remains intact throughout the chemical modification.
Research Support: This work was partially supported by the Dr. Jack Krohmer Professorship Funds.
http://jnumedmtg.snmjournals.org/cgi/content/meeting_abstract/55/1_MeetingAbstracts/1185
All the best,
John
I'll answer my own question,
We're just scratching the surface of anti PS.
Virus like particles, phosphatidylserine and nanomed, it's about that time, IMO.
I've got a thought, if one can target PS to block it, then isn't also possible to attach and promote it? When auspiciously appropriate anyway...
Nanomedicine. 2014 Jul;10(5):981-9. doi: 10.1016/j.nano.2014.02.008. Epub 2014 Mar 1.
aEnv-decorated phosphatidylserine liposomes trigger phagocytosis of HIV-virus-like particles in macrophages.
Gramatica A1, Petazzi RA2, Lehmann MJ3, Ziomkowska J1, Herrmann A1, Chiantia S4.
Author information
Abstract
Macrophages represent an important cellular target of HIV-1. Interestingly, they are also believed to play a potential role counteracting its infection. However, HIV-1 is known to impair macrophage immune functions such as antibody-mediated phagocytosis. Here, we present immunoliposomes that can bind HIV-1 virus-like particles (HIV-VLPs) while being specifically phagocytosed by macrophages, thus allowing the co-internalization of HIV-VLPs. These liposomes are decorated with anti-Env antibodies and contain phosphatidylserine (PS). PS mediates liposome internalization by macrophages via a mechanism not affected by HIV-1. Hence, PS-liposomes mimic apoptotic cells and are internalized into the macrophages due to specific recognition, carrying the previously bound HIV-VLPs. With a combination of flow cytometry, confocal live-cell imaging and electron microscopy we demonstrate that the PS-immunoliposomes presented here are able to elicit efficient HIV-VLPs phagocytosis by macrophages and might represent a new nanotechnological approach to enhance HIV-1 antigen presentation and reduce the ongoing inflammation processes.
FROM THE CLINICAL EDITOR:
This team of authors demonstrate that specific phosphatidylserin immunoliposomes are able to elicit efficient phagocytosis of HIV-virus-like particle by macrophages and might represent a new nanomedicine approach to enhance HIV-1 antigen presentation and reduce ongoing inflammation processes.
Copyright © 2014 Elsevier Inc. All rights reserved.
http://www.ncbi.nlm.nih.gov/pubmed/24589930
All the best,
John
Okay, and thank you! EOM
Exwannabe(edit),
Can you please respond to this observation from CP..
TIA,
All the best,
John
Yes, and thank you..
I've read that their dendritic cell vaccine (DCVax-L) is to weak to have any significant effect to GBM anyway. ImmunoCellular Therapeutics has a similar drug that failed in an identical study last year.
If you haven't noticed, I'm really interested in Statin/Bavituximab/Cotara synergies. I feel that Peregrine might have been well advised to think outside the box and weigh this option, instead of taking the high road with PD-1 combos, IMO..
I bet it eventually happens, maybe after Bavituximab's approval :)
All the best,
John
The Glioblastoma Multiforme (GBM) treatment market is forecast to grow rapidly from $301 million in 2013 to $623 million by 2020..
Lastly, and not to bore you, but recombinant proteins would be used in your "live" cell scenario for fluorescent tagging of live cells..
Anyway, you asked :)
All the best,
John
In reality, most immunohistochemist, microbiologist and old school researchers prefer Immunostaining as a way to view biomolecules and cellular structure. The technique is called "Immunofluorescence", by way of fluorescent staining, and I'll guarantee you that all the information, and research study descrips of Bavituximab's MOA have been viewed this way.. In my opinion, anyway.
I would certainly expect FTM and MicrobeMan to concur..
All the best,
John
"Beta"
As in Beta "blocker"? Heart arrhythmia..
As in "Beta Receptors" which are found on cells of the heart muscle..
As in Beta "radiation"?
As in Beta "Particles"?
As in beta-get living longer :))
All the best,
John
No no, I know science, not develop a better mouse trap. My money's here.
Btw, their inhibitor seems upstream to Bavituximab, and I've mentioned in the past just this scenario. I can tell you my opinion of how it is if anyone's interested?
Let me know if you want the post.
If anti PS is real then others will try to find a better way to skin a cat. Well anti-ps just got legitimized, IMO.
All the best,
John
LOL,
Anyone want to hear my scientific opinion?
I'd be cautious of what they're not telling the general public.
Such as antigenic drift, and viral recombination.
Yes, these are terms that are typically associated with influenza mutation. however, every virus known to man has mutated and survived using the same mechanisms.
It's happening with each and every African out-break, IMO. And the reason why this outbreak has been the most deadly, IMO..
Bad decision to move it...
All the best,
John
Bavituximab wouldn't be a good approach for influenza virus, but for Ebola, yes, IMO.
The influenza virus doesn't attack host cells through PS receptor (proteins) (update)as does Flaviviruses (Ebola), IMO.
All the best,
John
A parallel for Ebola infectivity would be somewhere between HIV and meningitis, IMO..
El'Wooky is not far off, IMO.
All the best,
John
PC11,
Not a typo or joke,
I wouldn't suggest it unless there were some method to the madness :)
Statin drugs and Bavituximab have always been intriguing by way of
immunomodulatory effect, however the synergy between Bavituximab and Crestor would be different altogether, in regards to Ebola.
It's widely recognized that "viral Ebola replication" requires the cholesterol transporter protein NPC1.
NPCI demonstrates an affinity to bind with glycoprotein, and it's the process of cholesterol transport and GP binding that allow for viral entry, and replication.
I'm suggesting that in combination, Crestor and Bavituximab would both diminish and block these entry point pathways.
Crestor by way of diminished cholesterol transport proteins, and Bavituximab through GP differentiation by way of TIM1, TIM4 binding proteins and attachment to Phosphatidylserine.
Theoretically, Crestor and Bavituximab would overwhelm the "enveloped virulent cell", and block replication.
Or more simply put, take away the "keys" to the vehicle that the virus uses to drive.
All the best,
John
Bavituximab + Crestor combo trial and Ebola...
Call me crazy,
Until it happens.
All the best,
John
Isn't completed trial data a "material event"? Help me here...
Otherwise they could just hold on to negative results, in order to not jeopardize Phase III enrollment, IMO..
They definitely don't want negative PR at this point.
On the other hand, now would be the time to release good data, as a way to substantiate Bavituximab.
All the best,
John
Common cold & Bavituximab
Yes, just like aspirin, there will be indirect discoveries.
BTW, what kind of sentence structure did i just use? not appositive, but??? Clue: think clause.. LOL
All the best,
John
Well since Jakedogman isn't posting much, I thought I'd "contrarily" step in :)
Speaking of Anti PS, I don't recall anyone discussing Dr. Hutchins comment regarding "anti viral"..
Specifically this comment:
"As part of a broader strategy in the anti-viral area, researchers presented data showing that a PS-binding antibody inhibited HIV infection of cells by indirectly blocking viral receptors used by HIV to facilitate infection."
This is an awesome statement, and what else does Bavituximab "indirectly block?"
Aging?
All the best,
John