Mutant p53 tends to form aggregates with amyloid properties, especially amyloid oligomers inside the nucleus, which are believed to cause oncogenic gain-of-function (GoF).

Despite being referred to as the guardian of the genome, when impacted by mutations, p53 can lose its protective functions and become a renegade. The malignant transformation of p53 occurs on multiple levels, such as altered DNA binding properties, acquisition of novel cellular partners, or associating into different oligomeric states. The consequences of these transformations can be catastrophic. Ongoing studies have implicated different oligomeric p53 species as having a central role in cancer biology; however, the correlation between p53 oligomerization status and oncogenic activities in cancer progression remains an open conundrum. In this review, we summarize the roles of different p53 oligomeric states in cancer and discuss potential research directions for overcoming aberrant p53 function associated with them. We address how misfolding and prion-like amyloid aggregation of p53 seem to play a crucial role in cancer development. The misfolded and aggregated states of mutant p53 are prospective targets for the development of novel therapeutic strategies against tumoral diseases.

Background: Neurotoxic chemical warfare agents can be classified as some of the most dangerous chemicals for humanity. The most effective of those agents are the organophosphates (OPs) capable of restricting the enzyme acetylcholinesterase (AChE), which in turn controls the nerve impulse transmission. When AChE is inhibited by OPs, its reactivation can be usually performed through cationic oximes. However, until today it has not been developed one universal defense agent, with complete effective reactivation activity for AChE inhibited by any of the many types of existing neurotoxic OPs. For this reason, before treating people intoxicated by an OP, it is necessary to determine the neurotoxic compound that was used for contamination, in order to select the most effective oxime. Unfortunately, this task usually requires a relative long time, raising the possibility of death. Cationic oximes also display a limited capacity of permeating the blood-brain barrier (BBB). This fact compromises their capacity of reactivating AChE inside the nervous system. Methods: We performed a comprehensive search on the data about OPs available on the scientific literature today in order to cover all the main drawbacks still faced in the research for the development of effective antidotes against those compounds. Results: Therefore, this review about neurotoxic OPs and the reactivation of AChE, provides insights for the new agents’ development. The most expected defense agent is a molecule without toxicity and effective to reactivate AChE inhibited by all neurotoxic OPs. Conclusion: To develop these new agents it is necessary the application of diverse scientific areas of research, especially theoretical procedures as computational science (computer simulation, docking and dynamics); organic synthesis; spectroscopic methodologies; biology, biochemical and biophysical information; medicinal chemistry, pharmacology and toxicology.

The chemical warfare agents and neurotoxic agents are an important threat to people all over the world, and require special attention because they are highly dangerous. Most of these agents are neurotoxic organophosphorus compounds (OP), which inhibit the enzyme acetylcholinesterase (AChE), which is responsible for controlling the transmission of nerve impulses. To be inhibited by these compounds, AChE can sometimes be reactivated using cationic oximes, which are the most used substances for this reactivation. Until today there have not been discovered agents for complete treatment of poisoning by all OPs. For this reason, the treatment of intoxicated people requires the determination of the absorbed OP, in order to select the appropriate activator, a process that usually requires long time and may cause death. Therefore, this study aims to do a review on the OPs used as chemical warfare agents and the process of inhibition and reactivation of AChE, especially to motivate the development of new agents for defense against chemical weapons, a process that is very important for protecting all humanity.