Team:Goettingen/project overview/perspectives

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<p>We have attained two milestones as far as the applications of our project is concerned. First,is the generation of peptides with an affinity to fungal surface molecules and second, is the  proof of principle that our selection scheme can be used to generate peptides with affinity to a molecule under scrutiny. Both milestones hold promise but before that, we would like to elaborate on the future scope of the first milestone since it bears relevance to medicine and healthcare.</p><br />
<p>We have attained two milestones as far as the applications of our project is concerned. First,is the generation of peptides with an affinity to fungal surface molecules and second, is the  proof of principle that our selection scheme can be used to generate peptides with affinity to a molecule under scrutiny. Both milestones hold promise but before that, we would like to elaborate on the future scope of the first milestone since it bears relevance to medicine and healthcare.</p><br />
 +
 +
<h2 id="diagnostics">Applications in Diagnostics</h2>      <br />   
 +
<h3>Lowering costs</h3><br />
 +
<p>The attachment of a chemical moiety that emits a quantifiable signal (a
 +
 +
fluorescent, enzymatic or luminiscent moiety) to our peptides can lead to an
 +
 +
alternative diagnostic method to antibody and antibody fragments with the added
 +
 +
benefit of the relative low cost of production and modification of small peptides. This cost reduction may
 +
 +
help to spread this diagnostic tool to the markets of the developing world, where
 +
 +
fungal infections have the largest mortality rates and were health care is
 +
 +
largely affected by economic constraints. Moreover, if the peptides prove to have a high species-specificity, the diagnosis based on them may give more information for a proper therapy choice, potentially reducing the toxicity risks associated with the use of broad spectrum antimycotics.</p><br />
 +
 +
 +
<h3><i>In vivo</i> diagnosis and the potential of artificial selection</h3><br />
 +
<p>Short peptides are currently being used as diagnostic tools for certain kind
 +
 +
of cancers. These peptides are naturally produced by humans
 +
 +
and have their natural binding proteins in the surface of cells; however, they
 +
 +
have been optimized to increase their half-life and their affinity towards their
 +
 +
natural target, and they also have been modified with radionuclides that make it
 +
 +
possible to detect the location of tumors -cells were their binding proteins are
 +
 +
overrepresented- with PET or SECT imaging.</p><br />
 +
 +
<p>The most common isotopically labelled peptide used for diagnosisis a <sup>111</sup>In-labelled somatostatin analogue, known as OctreoScan<sup>TM</sup>, which is used to diagnose a variety of tumors. Other peptides under
 +
 +
develompent are cholecystokinin/gastrin analogues, glucagon-like peptide-1,
 +
 +
bombesin, chemokine receptor CXCR4 targeting peptides, RGD peptides, exendin,
 +
 +
Substance P, LHRH, neurotensin, &alpha;-M2, &alpha;-M2H and VIP.</p>  <br />
 +
 +
<p>Following the same rationale, our artificially selected peptides can be modified and optimized to increase their binding affinity and their half-life. The peptides can then be tagged with radionuclides to enable the diagnosis by imaging techniques. The results of such a diagnostic method will give more information about the localization and spread of the fungal infection inside the patient's body than any of the currently available diagnostic methods.</p><br /><br />
 +
<hr>
 +
<br />
 +
 +
<h2 id="therapeutics">Therapeutic Applications</h1><br />   
 +
 +
<h3>Fungal Infections and  the branches of the immune system that deal with them</h3><br />
 +
<p>
 +
The peptides we developed have significant applications from a clinical standpoint. It has been observed in that individuals suffering from deficiencies in antibody and complement mediated cytotoxicity are less vulnerable to fungal infections than the ones suffering from phagocytic defects. Moreover studies have shown that neutrophils are pivotal in fending off fungal infections.  This is further supported by the fact that many cases of fungal infections were following a period of neutropenia (low neutrophil count in blood).</p> <br />
 +
<p>Two vital principles can be gathered from the aforementioned information:</p> <br />
 +
<ul>
 +
<li>- Phagocytes (especially neutrophils) play a very important role in the resolution (clearance) of the fungal infection.</li> <br />
 +
<li>- Antibodies and the complement system are not that effective against fungal pathogens due to the surface of these pathogens being unfriendly to binding.</li><br />
 +
 +
<p>As such, the modulation of these branches of the immune system should aid in the resolution of the disease.  It's important to mention that since most patients suffering from invasive mycoses are immuno-compromised and that there are different types of immunodeficiencies. Depending upon which branch is dysfunctional, an appropriate strategy of immunomodulation can be adopted.</p> <br />
 +
 +
 +
 +
<h3>Modifications to the peptide so that it  can emulate an antibody's stimulatory function</h3><br />
 +
<p>
 +
The novelty in our peptides is that it CAN bind to the fungal surface and it can be further modified using the Fc(constant) region of the IgG1 or IgG3 antibody subtype (IgG2a in mice). This region is important as it is recognized by the effector cells (neutrophils and macrophages) of the immune system and thereafter, leads to the death of the target cell. This way, not only can it bind to fungal pathogens but can also “draw attention” towards itself from the immune system. In addition to this, the constant region can also activate the compliment cascade via the "classical" pathway. Essentially, this set-up functions as a modified antibody with an added bonus of greater affinity. </p> <br />
 +
 +
 +
 +
<h3>Enhancement of immune response in immunodeficient individuals</h3><br />
 +
<p>
 +
As for the stimulation of the immune system in case of individuals with immunodeficiencies, the use of adjuvants (immune response enhancers) to augment the response is one strategy. In addition to this, natural immuno-modulatory molecules called cytokines (such as Interleukin-1 and Interferon-gamma) to stimulate the appropriate branches of the immune system can be employed as well. </p>
 +
 +
 +
<br />
 +
<h3>Homing the anti-fungal drug to the site of infection</h3><br />
 +
<p>Anti-mycotics have such as Amphotericin B are fluconazole have been used extensively to treat fungal infections. While they’ve been effective, they are more toxic to the human body than antibiotics that kill bacteria. This is due to the fact that bacteria are more dissimilar to humans than fungi are. As a result, it’s relatively simpler to find targets for antibiotics than anti-mycotics. Simply put, the more we humans have in common with a pathogen, the greater is the difficulty in coming up with a drug that harms only one (in other words, there is a need for selective toxicity).</p>
 +
<br />
 +
<p>Thus, yet another potential application of the novel peptides we developed is that they can act as “guides” to these molecules thereby reducing side-effects due to the drug in question.</p>
 +
<br />
 +
<hr>
 +
<h2>References</h2>
 +
<br /><br />
 +
<ul>
 +
<li>
 +
1. Raghavan M, Bjorkman P (1996). "Fc receptors and their interactions with immunoglobulins". Annu Rev Cell Dev Biol 12: 181–220.
 +
<br /><br /></li>
 +
<li>
 +
2. Swanson J, Hoppe A (2004). "The coordination of signaling during Fc receptor-mediated phagocytosis", J Leukoc Biol 76 (6): 1093–103. doi:10.1189/jlb.0804439
 +
<br /><br /></li>
 +
<li>
 +
3. Pan L, Pei P (2003). "Signaling transduction by IgG receptors". Chin Med J (Engl) 116 (4): 487–94.
 +
<br /><br /></li>
 +
<li>
 +
4.  Mueller-Loebnitz C, Ostermann H, Franzke A,Loeffler J, Uharek L, Topp M, and  Einsel H: Immunological Aspects of Candida and Aspergillus Systemic Fungal Infections: Interdisciplinary Perspectives on Infectious Diseases, Volume 2013 (2013), Article ID 102934
 +
<br /><br /></li>
 +
<li>5. Fani, M., et al., (2012), Radiolabeled peptides: valuable tools for the detection and treatment of cancer, <i>Theranostics</i>, 2(5).</li><br /><br />
 +
<li>6. Laverman, P., (2012), Radiolabelled peptides for oncological diagnosis, <i>Eur J Nucl Med Mol Imaging</i>, 39 (Suppl I).</li>
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</ul>
 +
 +
 +
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Revision as of 11:30, 10 October 2014

Project




Further perspectives



We have attained two milestones as far as the applications of our project is concerned. First,is the generation of peptides with an affinity to fungal surface molecules and second, is the proof of principle that our selection scheme can be used to generate peptides with affinity to a molecule under scrutiny. Both milestones hold promise but before that, we would like to elaborate on the future scope of the first milestone since it bears relevance to medicine and healthcare.


Applications in Diagnostics


Lowering costs


The attachment of a chemical moiety that emits a quantifiable signal (a fluorescent, enzymatic or luminiscent moiety) to our peptides can lead to an alternative diagnostic method to antibody and antibody fragments with the added benefit of the relative low cost of production and modification of small peptides. This cost reduction may help to spread this diagnostic tool to the markets of the developing world, where fungal infections have the largest mortality rates and were health care is largely affected by economic constraints. Moreover, if the peptides prove to have a high species-specificity, the diagnosis based on them may give more information for a proper therapy choice, potentially reducing the toxicity risks associated with the use of broad spectrum antimycotics.


In vivo diagnosis and the potential of artificial selection


Short peptides are currently being used as diagnostic tools for certain kind of cancers. These peptides are naturally produced by humans and have their natural binding proteins in the surface of cells; however, they have been optimized to increase their half-life and their affinity towards their natural target, and they also have been modified with radionuclides that make it possible to detect the location of tumors -cells were their binding proteins are overrepresented- with PET or SECT imaging.


The most common isotopically labelled peptide used for diagnosisis a 111In-labelled somatostatin analogue, known as OctreoScanTM, which is used to diagnose a variety of tumors. Other peptides under develompent are cholecystokinin/gastrin analogues, glucagon-like peptide-1, bombesin, chemokine receptor CXCR4 targeting peptides, RGD peptides, exendin, Substance P, LHRH, neurotensin, α-M2, α-M2H and VIP.


Following the same rationale, our artificially selected peptides can be modified and optimized to increase their binding affinity and their half-life. The peptides can then be tagged with radionuclides to enable the diagnosis by imaging techniques. The results of such a diagnostic method will give more information about the localization and spread of the fungal infection inside the patient's body than any of the currently available diagnostic methods.




Therapeutic Applications


Fungal Infections and the branches of the immune system that deal with them


The peptides we developed have significant applications from a clinical standpoint. It has been observed in that individuals suffering from deficiencies in antibody and complement mediated cytotoxicity are less vulnerable to fungal infections than the ones suffering from phagocytic defects. Moreover studies have shown that neutrophils are pivotal in fending off fungal infections. This is further supported by the fact that many cases of fungal infections were following a period of neutropenia (low neutrophil count in blood).


Two vital principles can be gathered from the aforementioned information:


  • - Phagocytes (especially neutrophils) play a very important role in the resolution (clearance) of the fungal infection.

  • - Antibodies and the complement system are not that effective against fungal pathogens due to the surface of these pathogens being unfriendly to binding.

    • As such, the modulation of these branches of the immune system should aid in the resolution of the disease. It's important to mention that since most patients suffering from invasive mycoses are immuno-compromised and that there are different types of immunodeficiencies. Depending upon which branch is dysfunctional, an appropriate strategy of immunomodulation can be adopted.


    Modifications to the peptide so that it can emulate an antibody's stimulatory function


    The novelty in our peptides is that it CAN bind to the fungal surface and it can be further modified using the Fc(constant) region of the IgG1 or IgG3 antibody subtype (IgG2a in mice). This region is important as it is recognized by the effector cells (neutrophils and macrophages) of the immune system and thereafter, leads to the death of the target cell. This way, not only can it bind to fungal pathogens but can also “draw attention” towards itself from the immune system. In addition to this, the constant region can also activate the compliment cascade via the "classical" pathway. Essentially, this set-up functions as a modified antibody with an added bonus of greater affinity.


    Enhancement of immune response in immunodeficient individuals


    As for the stimulation of the immune system in case of individuals with immunodeficiencies, the use of adjuvants (immune response enhancers) to augment the response is one strategy. In addition to this, natural immuno-modulatory molecules called cytokines (such as Interleukin-1 and Interferon-gamma) to stimulate the appropriate branches of the immune system can be employed as well.


    Homing the anti-fungal drug to the site of infection


    Anti-mycotics have such as Amphotericin B are fluconazole have been used extensively to treat fungal infections. While they’ve been effective, they are more toxic to the human body than antibiotics that kill bacteria. This is due to the fact that bacteria are more dissimilar to humans than fungi are. As a result, it’s relatively simpler to find targets for antibiotics than anti-mycotics. Simply put, the more we humans have in common with a pathogen, the greater is the difficulty in coming up with a drug that harms only one (in other words, there is a need for selective toxicity).


    Thus, yet another potential application of the novel peptides we developed is that they can act as “guides” to these molecules thereby reducing side-effects due to the drug in question.


    References



    • 1. Raghavan M, Bjorkman P (1996). "Fc receptors and their interactions with immunoglobulins". Annu Rev Cell Dev Biol 12: 181–220.

    • 2. Swanson J, Hoppe A (2004). "The coordination of signaling during Fc receptor-mediated phagocytosis", J Leukoc Biol 76 (6): 1093–103. doi:10.1189/jlb.0804439

    • 3. Pan L, Pei P (2003). "Signaling transduction by IgG receptors". Chin Med J (Engl) 116 (4): 487–94.

    • 4. Mueller-Loebnitz C, Ostermann H, Franzke A,Loeffler J, Uharek L, Topp M, and Einsel H: Immunological Aspects of Candida and Aspergillus Systemic Fungal Infections: Interdisciplinary Perspectives on Infectious Diseases, Volume 2013 (2013), Article ID 102934

    • 5. Fani, M., et al., (2012), Radiolabeled peptides: valuable tools for the detection and treatment of cancer, Theranostics, 2(5).


    • 6. Laverman, P., (2012), Radiolabelled peptides for oncological diagnosis, Eur J Nucl Med Mol Imaging, 39 (Suppl I).



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