AZT is used successfully as part of Highly Active Anti-Retroviral Therapy (HAART) to control the level of the human immunodeficiency virus in HIV-infected individuals. However, long-term use of AZT may lead to side-effects in some patients. David Samuels and coworkers are interested in finding out whether the toxic side effects of AZT can eventually be minimized or even eliminated. For this purpose, they have been developing a detailed computational model that allows scientists to simulate the biochemical reactions that take place when AZT is metabolized in cells, including their mitochondria, under different metabolic conditions. Drugs like AZT may interfere with DNA replication in the mitochondria, the energy factories of our cells, and can lead to potentially fatal side effects in patients undergoing HAART treatment.
Samuels, assistant professor at VBI, commented: "HAART is one of the biggest success stories in modern medicine. The goal of our work is to help improve this successful treatment by understanding the toxic effects that AZT can have in some people. There are many different ways that AZT could possibly interfere with mitochondria to cause the toxic side-effects. Our job is to model these proposed toxicity mechanisms to see which ones could actually lead to the mitochondrial defects found in AIDS patients." He added: "It is possible that no single mechanism is responsible for the toxicity, but that instead a combination of multiple effects is needed. That is the kind of problem that needs a systems biology approach."
When AZT reaches a cell, it is subject to some of the same metabolic modifications or phosphorylation events that are encountered by the four naturally occurring deoxynucleosides, the building blocks used to make DNA. However, modified AZT molecules lack a specific chemical group (a hydroxyl group) that would allow DNA replication to continue. This results in premature termination of DNA synthesis. It is thought that the triphosphorylated form of AZT can enter the mitochondrial matrix, the inner core of the mitochondrion, and disrupt the replication of mitochondrial DNA by prematurely terminating DNA synthesis.
Samuels added: "We're just starting our work. It is too early to say what the mechanism of mitochondrial toxicity of AZT is. The inhibition of deoxynucleoside metabolism is one possibility. The incorporation of AZT into mitochondrial DNA is another." He added: "The detailed computational model that we have developed should allow researchers to explore different hypotheses as to why AZT can lead to such debilitating side effects in some patients undergoing anti-retroviral treatment."
About the Virginia Bioinformatics Institute
The Virginia Bioinformatics Institute (VBI) at Virginia Tech has a research platform centered on understanding the "disease triangle" of host–pathogen–environment interactions in plants, humans and other animals. By successfully channeling innovation into transdisciplinary approaches that combine information technology and biology, researchers at VBI are addressing some of today's key challenges in the biomedical, environmental and plant sciences.
Barry Whyte | EurekAlert!
Cancer diagnosis: no more needles?
25.05.2018 | Christian-Albrechts-Universität zu Kiel
Less is more? Gene switch for healthy aging found
25.05.2018 | Leibniz-Institut für Alternsforschung - Fritz-Lipmann-Institut e.V. (FLI)
The more electronics steer, accelerate and brake cars, the more important it is to protect them against cyber-attacks. That is why 15 partners from industry and academia will work together over the next three years on new approaches to IT security in self-driving cars. The joint project goes by the name Security For Connected, Autonomous Cars (SecForCARs) and has funding of €7.2 million from the German Federal Ministry of Education and Research. Infineon is leading the project.
Vehicles already offer diverse communication interfaces and more and more automated functions, such as distance and lane-keeping assist systems. At the same...
A research team led by physicists at the Technical University of Munich (TUM) has developed molecular nanoswitches that can be toggled between two structurally different states using an applied voltage. They can serve as the basis for a pioneering class of devices that could replace silicon-based components with organic molecules.
The development of new electronic technologies drives the incessant reduction of functional component sizes. In the context of an international collaborative...
At the LASYS 2018, from June 5th to 7th, the Laser Zentrum Hannover e.V. (LZH) will be showcasing processes for the laser material processing of tomorrow in hall 4 at stand 4E75. With blown bomb shells the LZH will present first results of a research project on civil security.
At this year's LASYS, the LZH will exhibit light-based processes such as cutting, welding, ablation and structuring as well as additive manufacturing for...
There are videos on the internet that can make one marvel at technology. For example, a smartphone is casually bent around the arm or a thin-film display is rolled in all directions and with almost every diameter. From the user's point of view, this looks fantastic. From a professional point of view, however, the question arises: Is that already possible?
At Display Week 2018, scientists from the Fraunhofer Institute for Applied Polymer Research IAP will be demonstrating today’s technological possibilities and...
So-called quantum many-body scars allow quantum systems to stay out of equilibrium much longer, explaining experiment | Study published in Nature Physics
Recently, researchers from Harvard and MIT succeeded in trapping a record 53 atoms and individually controlling their quantum state, realizing what is called a...
25.05.2018 | Event News
02.05.2018 | Event News
13.04.2018 | Event News
25.05.2018 | Event News
25.05.2018 | Machine Engineering
25.05.2018 | Life Sciences