{"id":435,"date":"2016-12-20T02:57:21","date_gmt":"2016-12-20T07:57:21","guid":{"rendered":"http:\/\/www.creative-peptides.com\/blog\/?p=435"},"modified":"2016-12-20T02:58:01","modified_gmt":"2016-12-20T07:58:01","slug":"implications-for-the-use-and-study-of-amyloid-in-therapeutics-bionanomaterials-and-biophysics","status":"publish","type":"post","link":"https:\/\/www.creative-peptides.com\/blog\/implications-for-the-use-and-study-of-amyloid-in-therapeutics-bionanomaterials-and-biophysics\/","title":{"rendered":"Implications for the use and study of amyloid in therapeutics, bionanomaterials, and biophysics"},"content":{"rendered":"

Therapeutics<\/i><\/b><\/em><\/strong>
\n<\/i><\/b><\/em><\/strong>The structure of amyloid fibrils has been sought for a number of proteins involved\u00a0in amyloid diseases. One of the main goals for determining the structure of amyloid has
\nbeen for drug design; once the structure of the fibrils is known, specific drugs can be designed to inhibit the formation of these toxic structures.\u00a0However, if the\u00a0structures that amyloidogenic proteins and peptides form are so dependent on their\u00a0environment, they likely form many different structures in vivo<\/i><\/em>, based on the different\u00a0cellular compartments or extracellular space in which they form and\/or deposit.\u00a0Additionally, interactions between a drug and an amyloidogenic protein can change the\u00a0energy landscape as well such that a different amyloid conformation could become more\u00a0stable than that formed without the drug, which could be harmful or beneficial to the organism\u2014it would be hard to predict this a priori<\/i><\/em>. Therefore, it might be more\u00a0beneficial to target therapeutics toward the complete inhibition of any type of\u00a0aggregation\u00a0by disease-related amyloid proteins<\/a>, which is very challenging, or even something more\u00a0upstream from fibril formation in disease progression.<\/p>\n

Bionanomaterials<\/i><\/b><\/em><\/strong>
\n<\/i><\/b><\/em><\/strong>Since amyloid fibrils are ordered self-assemblies, their use as bionanomaterials is\u00a0of great interest.\u00a0Amyloid could in principle be used as nanowires, gels, liquid\u00a0crystals, and structural scaffolds. However, a better understanding of the energetics of\u00a0amyloid will likely be required before any real applications result. As has been\u00a0mentioned, the structure of many pathological amyloid fibrils are highly sensitive to the\u00a0environment in which they are formed. Changing environmental conditions after the\u00a0fibrils have formed can have a profound effect on their structure and stability, especially\u00a0over a long period of time. For instance, \u03b22-microglobulin fibrils formed at low pH\u00a0dissolve when brought back to neutral conditions.\u00a0Native amyloid may be better suited\u00a0as a bionanomaterial because it has evolved to form amyloid, so it is likely that the\u00a0structures formed are less frustrated and less susceptible to major changes in energy and\u00a0structure upon an environmental change. Therefore, it is very important to carefully\u00a0choose the amino acid sequences one uses to make amyloid-like bionanomaterials and to\u00a0avoid using de novo <\/i><\/em>designed sequences or disease-related amyloid sequences as a\u00a0starting point if such sequences exhibit rough, highly concentration dependent amyloid\u00a0landscapes.<\/p>\n

Biophysics<\/i><\/b><\/em><\/strong>
\n<\/i><\/b><\/em><\/strong>As mentioned before, the stability of amyloid fibrils can be examined using fibril\u00a0denaturation with chaotropes. To extract thermodynamic parameters from denaturation\u00a0curves, approximations of two-state behavior are typically made. This type of analysis\u00a0assumes there are no intermediates along the folding pathway, the folded state all adopts\u00a0a single structure, and that the system is at equilibrium at the time of measurement.\u00a0However, as discussed earlier, changing the environment of amyloid fibrils has a strong\u00a0impact on the structure that it adopts. Adding chaotrope may change which structure is\u00a0most stable, which would impact all of the assumptions made in doing this two-state\u00a0approximation of amyloid denaturation. One must therefore be extremely careful when\u00a0determining the stability of amyloid fibrils that these assumptions are in fact met (that the\u00a0system is at equilibrium when measurements are taken and that the same structure is\u00a0populated as chaotrope is added) before trying to obtain thermodynamic constants from\u00a0amyloid denaturation curves.<\/p>\n

Conclusion<\/b><\/strong>
\n<\/b><\/strong>It is important to understand how amyloid proteins transform from soluble\u00a0monomeric units to insoluble, structured fibrils that cause disease so that viable treatment\u00a0options for such maladies can be discovered. However, the polymerization mechanism\u00a0most often used to describe amyloid formation, a nucleated polymerization, is likely too\u00a0simplistic to describe the complexities of aggregation of pathological amyloid proteins.\u00a0During a given in vitro <\/i><\/em>aggregation reaction, species other than fibrils and monomers are\u00a0observed, and the structures of aggregates formed depend strongly on the conditions in\u00a0which the aggregation occurs and on the monomer concentration. This indicates that the\u00a0folding energy landscapes of pathological amyloid proteins are not funneled, as would be\u00a0the case for a typical protein; rather they are likely frustrated, containing many minima\u00a0associated with different aggregate conformations that have similar energies. Therefore,\u00a0slightly changing the conditions leads to a differently structured end product. For native\u00a0amyloid, which has evolved its sequence to carry out its function from an amyloid\u00a0structure, the folding energy landscape is likely funneled to avoid other structures that\u00a0might not carry out its function properly. This has implications in the way we think\u00a0about amyloid and study it biophysically, the use of amyloid fibrils for its material\u00a0properties, and the design of therapeutics for treating amyloid diseases.<\/p>\n

 <\/p>\n

Reference:<\/p>\n

Sarah J. Siegel. Structure and Energetics of Amyloid<\/p>\n","protected":false},"excerpt":{"rendered":"

Therapeutics The structure of amyloid fibrils has been sought for a number of proteins involved\u00a0in amyloid diseases. One of the main goals for determining the structure of amyloid has been …<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":[],"categories":[75],"tags":[80,79],"_links":{"self":[{"href":"https:\/\/www.creative-peptides.com\/blog\/wp-json\/wp\/v2\/posts\/435"}],"collection":[{"href":"https:\/\/www.creative-peptides.com\/blog\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.creative-peptides.com\/blog\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.creative-peptides.com\/blog\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.creative-peptides.com\/blog\/wp-json\/wp\/v2\/comments?post=435"}],"version-history":[{"count":2,"href":"https:\/\/www.creative-peptides.com\/blog\/wp-json\/wp\/v2\/posts\/435\/revisions"}],"predecessor-version":[{"id":437,"href":"https:\/\/www.creative-peptides.com\/blog\/wp-json\/wp\/v2\/posts\/435\/revisions\/437"}],"wp:attachment":[{"href":"https:\/\/www.creative-peptides.com\/blog\/wp-json\/wp\/v2\/media?parent=435"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.creative-peptides.com\/blog\/wp-json\/wp\/v2\/categories?post=435"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.creative-peptides.com\/blog\/wp-json\/wp\/v2\/tags?post=435"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}