Sandbox Reserved 1472: Difference between revisions

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== Relevance (Disease) ==

Disease causes cellular stress in organisms and because heat shock proteins function to protect proteins from stressed conditions they have relevance in many pathological processes like cancer, neurodegenerative disease, infectious agents and more<ref name="hoter" />.Because Hsp90 works so flexibly to stabilize proteins it becomes a problem by helping oncogenic proteins function. However this is also a potential tool in fighting cancer by Hsp90 inhibition. Hsp90 has a high basal expression compared to most other heat shock proteins. If the organism is not under environmental stress Hsp90 may not be needed at high levels for homeostasis~~. However~~ cancer cells are highly reliant on it. The largest interest in the recent study of Hsp90 is its use a cancer treatment.The two main natural inhibitors that can be used to inhibit Hsp90 are radicicol and geldanamycin. These inhibitors work by binding to Hsp90 where normally ATP would. These natural inhibitors have been studied in vitro and in vivo and have shown to affect cancer proliferation but they both have problems in regards to instability and toxicity<ref name="hoter" />. One method deal with the issue of toxicity and instability of these natural inhibitors is to alter them. This has been done with geldanamycin by switching its C17 with an allylamino group, this results in 17-AAG (17-allyl-17-demethoxygeldamycin). This has helped with the toxicity issue and 17-AAG has been used in phase I/II clinical trials<ref name="hoter" />. Another method that could be used to inhibit the Hsp90 system to attack cancer is to target other parts of the system rather than the ATP binding in the NTD of Hsp90. For instance, the interaction between Hsp90 and one of its main co-chaperones could be disrupted. This could lead to a narrowed impact on Hsp90 function and be less harmful to the body’s healthy cells. Cdc37 is an excellent example of a co-chaperone whose interaction with Hsp90 could be targeted and this would allow proteins other than Hsp90 dependent kinases to still function properly. Many of the kinase clients of Hsp90-Cdc37 are involved in the regulation of cellular responses and development and the proliferation of cancer cells are especially susceptible by their disruption<ref name="li">PMID:29699578</ref>. Three ways in which the Hsp90-Cdc37-client protein complex functioning could be interfered with are; targeting Cdc37, the interaction between Cdc37 and the client protein, or the interaction between Hsp90 and Cdc37. Cdc37 has an increased level in growing tissues and shows high expression in some tumor cells, it could be possible to limit Cdc37 through gene silencing techniques. Targeting Cdc37 client interaction could be done through disrupting the phosphorylation of Cdc37 that needs to happen to initiate its initial interaction with clients. There are already several disruptors molecules of Hsp90-Cdc37 interaction that have been identified or synthesized with multiple mechanisms of blocking, some like Cdc37-derived peptide Pep-1 simply binds to Hsp90 acting competitively against Cdc37 binding<ref name="li" />. Hsp90 has the potential to serve as an effective means in fighting cancer. Targeting the Hsp90-Cdc37 chaperone system could be used make Hsp90 a more precise weapon in this battle by limiting toxicity issues in normal cells.

Disease causes cellular stress in organisms and because heat shock proteins function to protect proteins from stressed conditions they have relevance in many pathological processes like cancer, neurodegenerative disease, infectious agents and more<ref name="hoter" />.Because Hsp90 works so flexibly to stabilize proteins it becomes a problem by helping oncogenic proteins function. However this is also a potential tool in fighting cancer by Hsp90 inhibition. Hsp90 has a high basal expression compared to most other heat shock proteins. If the organism is not under environmental stress Hsp90 may not be needed at high levels for homeostasis, however cancer cells are highly reliant on it. The largest interest in the recent study of Hsp90 is in its use as a cancer treatment.The two main natural inhibitors that can be used to inhibit Hsp90 are radicicol and geldanamycin. These inhibitors work by binding to Hsp90 where normally ATP would. These natural inhibitors have been studied in vitro and in vivo and have shown to affect cancer proliferation but they both have problems in regards to instability and toxicity<ref name="hoter" />. One method deal with the issue of toxicity and instability of these natural inhibitors is to alter them. This has been done with geldanamycin by switching its C17 with an allylamino group, this results in 17-AAG (17-allyl-17-demethoxygeldamycin). This has helped with the toxicity issue and 17-AAG has been used in phase I/II clinical trials<ref name="hoter" />. Another method that could be used to inhibit the Hsp90 system to attack cancer is to target other parts of the system rather than the ATP binding in the NTD of Hsp90. For instance, the interaction between Hsp90 and one of its main co-chaperones could be disrupted. This could lead to a narrowed impact on Hsp90 function and be less harmful to the body’s healthy cells. Cdc37 is an excellent example of a co-chaperone whose interaction with Hsp90 could be targeted and this would allow proteins other than Hsp90 dependent kinases to still function properly. Many of the kinase clients of Hsp90-Cdc37 are involved in the regulation of cellular responses and development and the proliferation of cancer cells are especially susceptible by their disruption<ref name="li">PMID:29699578</ref>. Three ways in which the Hsp90-Cdc37-client protein complex functioning could be interfered with are; targeting Cdc37, the interaction between Cdc37 and the client protein, or the interaction between Hsp90 and Cdc37. Cdc37 has an increased level in growing tissues and shows high expression in some tumor cells, it could be possible to limit Cdc37 through gene silencing techniques. Targeting Cdc37 client interaction could be done through disrupting the phosphorylation of Cdc37 that needs to happen to initiate its initial interaction with clients. There are already several disruptors molecules of Hsp90-Cdc37 interaction that have been identified or synthesized with multiple mechanisms of blocking, some like Cdc37-derived peptide Pep-1 simply binds to Hsp90 acting competitively against Cdc37 binding<ref name="li" />. Hsp90 has the potential to serve as an effective means in fighting cancer. Targeting the Hsp90-Cdc37 chaperone system could be used make Hsp90 a more precise weapon in this battle by limiting toxicity issues in normal cells.

== References ==

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 == Relevance (Disease) ==
-Disease causes cellular stress in organisms and because heat shock proteins function to protect proteins from stressed conditions they have relevance in many pathological processes like cancer, neurodegenerative disease, infectious agents and more<ref name="hoter" />.Because  Hsp90 works so flexibly to stabilize proteins it becomes a problem by helping oncogenic proteins function. However this is also a potential tool in fighting cancer by Hsp90 inhibition. Hsp90 has a high basal expression compared to most other heat shock proteins. If the organism is not under environmental stress Hsp90 may not be needed at high levels for homeostasis. However cancer cells are highly reliant on it. The largest interest in the recent study of Hsp90 is its use a cancer treatment.The two main natural inhibitors that can be used to inhibit Hsp90 are radicicol and geldanamycin. These inhibitors work by binding to Hsp90 where normally ATP would. These natural inhibitors have been studied in vitro and in vivo and have shown to affect cancer proliferation but they both have problems in regards to instability and toxicity<ref name="hoter" />. One method deal with the issue of toxicity and instability of these natural inhibitors is to alter them. This has been done with geldanamycin by switching its C17 with an allylamino group, this results in 17-AAG (17-allyl-17-demethoxygeldamycin). This has helped with the toxicity issue and 17-AAG has been used in phase I/II clinical trials<ref name="hoter" />. Another method that could be used to inhibit the Hsp90 system to attack cancer is to target other parts of the system rather than the ATP binding in the NTD of Hsp90. For instance, the interaction between Hsp90 and one of its main co-chaperones could be disrupted. This could lead to a narrowed impact on Hsp90 function and be less harmful to the body’s healthy cells. Cdc37 is an excellent example of a co-chaperone whose interaction with Hsp90 could be targeted and this would allow proteins other than Hsp90 dependent kinases to still function properly. Many of the kinase clients of Hsp90-Cdc37 are involved in the regulation of cellular responses and development and the proliferation of cancer cells are especially susceptible by their disruption<ref name="li">PMID:29699578</ref>. Three ways in which the Hsp90-Cdc37-client protein complex functioning could be interfered with are; targeting Cdc37, the interaction between Cdc37 and the client protein, or the interaction between Hsp90 and Cdc37. Cdc37 has an increased level in growing tissues and shows high expression in some tumor cells, it could be possible to limit Cdc37 through gene silencing techniques. Targeting Cdc37 client interaction could be done through disrupting the phosphorylation of Cdc37 that needs to happen to initiate its initial interaction with clients. There are already several disruptors molecules of Hsp90-Cdc37 interaction that have been identified or synthesized with multiple mechanisms of blocking, some like Cdc37-derived peptide Pep-1 simply binds to Hsp90 acting competitively against Cdc37 binding<ref name="li" />. Hsp90 has the potential to serve as an effective means in fighting cancer. Targeting the Hsp90-Cdc37 chaperone system could be used make Hsp90 a more precise weapon in this battle by limiting toxicity issues in normal cells.
+Disease causes cellular stress in organisms and because heat shock proteins function to protect proteins from stressed conditions they have relevance in many pathological processes like cancer, neurodegenerative disease, infectious agents and more<ref name="hoter" />.Because  Hsp90 works so flexibly to stabilize proteins it becomes a problem by helping oncogenic proteins function. However this is also a potential tool in fighting cancer by Hsp90 inhibition. Hsp90 has a high basal expression compared to most other heat shock proteins. If the organism is not under environmental stress Hsp90 may not be needed at high levels for homeostasis, however cancer cells are highly reliant on it. The largest interest in the recent study of Hsp90 is in its use as a cancer treatment.The two main natural inhibitors that can be used to inhibit Hsp90 are radicicol and geldanamycin. These inhibitors work by binding to Hsp90 where normally ATP would. These natural inhibitors have been studied in vitro and in vivo and have shown to affect cancer proliferation but they both have problems in regards to instability and toxicity<ref name="hoter" />. One method deal with the issue of toxicity and instability of these natural inhibitors is to alter them. This has been done with geldanamycin by switching its C17 with an allylamino group, this results in 17-AAG (17-allyl-17-demethoxygeldamycin). This has helped with the toxicity issue and 17-AAG has been used in phase I/II clinical trials<ref name="hoter" />. Another method that could be used to inhibit the Hsp90 system to attack cancer is to target other parts of the system rather than the ATP binding in the NTD of Hsp90. For instance, the interaction between Hsp90 and one of its main co-chaperones could be disrupted. This could lead to a narrowed impact on Hsp90 function and be less harmful to the body’s healthy cells. Cdc37 is an excellent example of a co-chaperone whose interaction with Hsp90 could be targeted and this would allow proteins other than Hsp90 dependent kinases to still function properly. Many of the kinase clients of Hsp90-Cdc37 are involved in the regulation of cellular responses and development and the proliferation of cancer cells are especially susceptible by their disruption<ref name="li">PMID:29699578</ref>. Three ways in which the Hsp90-Cdc37-client protein complex functioning could be interfered with are; targeting Cdc37, the interaction between Cdc37 and the client protein, or the interaction between Hsp90 and Cdc37. Cdc37 has an increased level in growing tissues and shows high expression in some tumor cells, it could be possible to limit Cdc37 through gene silencing techniques. Targeting Cdc37 client interaction could be done through disrupting the phosphorylation of Cdc37 that needs to happen to initiate its initial interaction with clients. There are already several disruptors molecules of Hsp90-Cdc37 interaction that have been identified or synthesized with multiple mechanisms of blocking, some like Cdc37-derived peptide Pep-1 simply binds to Hsp90 acting competitively against Cdc37 binding<ref name="li" />. Hsp90 has the potential to serve as an effective means in fighting cancer. Targeting the Hsp90-Cdc37 chaperone system could be used make Hsp90 a more precise weapon in this battle by limiting toxicity issues in normal cells.
 == References ==
 <references/>