Biotechnology - Yu.O. Sazykin 2006

General Biotechnology
Genomics and Proteomics
The Human Genome - Conformational Diseases

The umbrella term "conformational diseases" has recently emerged in scientific literature. It may encompass a multitude of yet undescribed disorders that are fundamentally novel in nature. Its Introduction into literature was directly prompted by observations of unusual infectious diseases in both animals and humans. The pathogen is transmitted from animals to humans, and the disease is invariably fatal. The histopathological picture reveals a spongy state of the grey and/or White matter OF the Brain ("transmissible spongiform encephalopathy"). Due to the lack of effective medications and control measures for the disease known as "mad cow disease," governments of various countries have limited themselves to banning the export of meat products from specific regions and culling infected animals. Cases in humans are relatively rare, but their incidence varies widely across different countries and regions.

Of particular interest is not only the degree of danger posed by the disease, but also the fundamental novelty of the molecular and biological data associated with it. Recent studies have shown that a new "world" of previously unknown infections, termed "conformational diseases," has been uncovered. Furthermore, several authors emphasize that everything currently known about conformational diseases may merely be "the tip of the iceberg."

Initially, this condition was classified among viral infections; however, it soon became clear that the CAUSATIVE AGENT OF scrapie in sheep—imported from Germany to Iceland for karakul sheep breeding—was an infectious agent devoid of Nucleic Acids. This completely shattered the conventional paradigms of biologists and physicians. A similar disease called "kuru," in which the infectious agent also lacks nucleic acids, was discovered among indigenous tribes living in remote areas of New Guinea who still practiced cannibalism.

To date, four variants of diseases with such an unusual infectious agent are known in humans (specifically Creutzfeldt-Jakob disease and kuru), along with several variants in wild, agricultural, and domestic animals. A correlation has been established between the spread of the disease in humans and the consumption of meat from livestock whose young were fed meat-and-bone meal and other slaughterhouse by-products of sheep, particularly sheep heads. Mild Processing technologies for by-products (aimed at increasing their nutritional value) increase the risk of epidemic outbreaks.

The infectious agent was isolated and proved to be a low-molecular-weight protein (27–30 kDa), designated as the "infectious prion protein." The term "prion" was proposed for the infectious unit. This word is formed as an anagram of the English phrase "proteinaceous infectious (particle)," emphasizing that this protein possesses self-infectious capabilities. Prion propagation occurs not through "de novo" synthesis, but via a conformational change of a normal protein precursor. Such a normal protein is found primarily in Nervous Tissue, where its Gene Expression is 50 times higher than in other tissues. This protein regulates circadian rhythms of activity and participates in the transmission of nerve impulses. The alteration of the normal protein's conformation by a prion causes the altered protein itself to transform into a prion. As a result, the concentration of the normal protein within The Cell decreases, while The amount of the prion correspondingly increases, leading to cell death. This process is schematically represented as follows:

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where PrPsc is the prion (sc — scrapie), and PrPc is the normal cellular protein (c — cell).

Some authors suggest that neuronal death in spongiform encephalopathies occurs via apoptosis.

Attempts to prevent and treat spongiform encephalopathies using A wide variety of compounds have been made repeatedly. Steroids, peanut oil, amphotericin B, dextran sulfate, and certain anthracyclines have been used for this purpose. However, these attempts have yielded no significant results, aside from a slight delay in The Development of clinical symptoms due to an extended incubation period, which does not indicate a selective effect on the prion. It is worth noting that PrPc and PrPsc are isoforms of the same protein; Antibodies against Prions are not produced, which significantly complicates Laboratory Diagnostics, immunoprophylaxis, and immunotherapy of prion diseases.

According to the official consensus of WHO experts, the development of highly effective, selective treatments for prion diseases must be based on data regarding the three-dimensional Structure of prions. The normal protein undergoing transformation (PrPc) contains four alpha-helical domains connected by disulfide bridges. In contrast, in the prion molecule (PrPsc)—which is the infectious isoform—only two domains remain alpha-helical, while the other two become beta-sheets. This may occur as a result of point Mutations in the gene encoding the PrPc protein. For example, it has been established that certain constitutive Proteins can change their shape and transform into deadly prions.

To combat prion diseases, The Use of antisense oligonucleotides to suppress the expression of relevant genes has been proposed. Another potential approach is the creation of a molecular "glue" that, upon crossing the Blood-brain barrier, would bind to the hydrophobic "core" of PrPc—i.e., stabilize the alpha-helices and prevent the transition of PrPc into PrPsc. Alternatively, it has been suggested to design a "glue" that would interact with the prion (PrPsc), "wrapping" around it and preventing its interaction with PrPc. These proposals remain quite Abstract for now, but they demonstrate modern approaches to treating recently discovered and unusual diseases.

Review Questions

1. What is the difference between targeted screening and traditional screening in the discovery and Selection of new drug candidates?

2. What is the difference between Research Methods in Genomics and those in Proteomics?

3. How can Genomics and proteomics be compared in terms of discovering and developing new drugs?

4. How is genomics classified according to the tasks set in this field?

5. What does the term "reverse genetics" mean?

6. What is the current Practical significance of advances in genomics for pharmacy?

7. What is meant by METABOLISM/2.html">THE CONCEPT OF gene "essentiality"?

8. What is the difference between ex vivo and In Vivo Gene therapy?

9. What are antisense oligonucleotides?

10. What is the unusual nature of conformational diseases?