The evolution of resistance to currently prescribed HIV-1 protease inhibitors is devastating to patients and is surprising given the way these drugs work. Protease inhibitors are all small-molecule, competitive, active-site inhibitors--low molecular weight compounds that fit squarely in the center of the active site of HIV-1 protease and prevent protein processing that is essential to the replication of the virus. It would seem as though mutations occurring in the protease that prevent drug binding and result in drug resistance would also prevent normal substrate binding, and thus compensatory changes in the substrate would be required for the virus to survive. However, research from the lab of Celia Schiffer at the University of Massachusetts Medical School has revealed a common structural theme in protease inhibitor resistance.
By comparing the structures of several substrate-protease complexes, they establish a "substrate envelope" to define the three-dimensional shape that is shared by all the substrates as they are bound in the active site. They then go on to define an "inhibitor envelope" that shows how numerous protease inhibitors fit only partially within the substrate envelope. Where the inhibitors protrude beyond the confines of the substrate envelope, there is the potential for unique molecular contacts to the protease. Also, when the protease mutates at unique sites that contact the inhibitor envelope but not the substrate envelope, drug resistance emerges. This general principle offers a rational basis for combating drug resistance more aggressively by preventing a common mode of escape. Such a tool would be of enormous benefit in the worldwide fight against AIDS.
Nancy M. King, Moses Prabu-Jeyabalan, Ellen A. Nalivaika, and Celia A. Schiffer: "Combating Susceptibility to Drug Resistance: Lessons from HIV-1 Protease"
Heidi Hardman | EurekAlert!
Correct connections are crucial
26.06.2017 | Charité - Universitätsmedizin Berlin
One gene closer to regenerative therapy for muscular disorders
01.06.2017 | Cincinnati Children's Hospital Medical Center
An international team of scientists has proposed a new multi-disciplinary approach in which an array of new technologies will allow us to map biodiversity and the risks that wildlife is facing at the scale of whole landscapes. The findings are published in Nature Ecology and Evolution. This international research is led by the Kunming Institute of Zoology from China, University of East Anglia, University of Leicester and the Leibniz Institute for Zoo and Wildlife Research.
Using a combination of satellite and ground data, the team proposes that it is now possible to map biodiversity with an accuracy that has not been previously...
Heatwaves in the Arctic, longer periods of vegetation in Europe, severe floods in West Africa – starting in 2021, scientists want to explore the emissions of the greenhouse gas methane with the German-French satellite MERLIN. This is made possible by a new robust laser system of the Fraunhofer Institute for Laser Technology ILT in Aachen, which achieves unprecedented measurement accuracy.
Methane is primarily the result of the decomposition of organic matter. The gas has a 25 times greater warming potential than carbon dioxide, but is not as...
Hydrogen is regarded as the energy source of the future: It is produced with solar power and can be used to generate heat and electricity in fuel cells. Empa researchers have now succeeded in decoding the movement of hydrogen ions in crystals – a key step towards more efficient energy conversion in the hydrogen industry of tomorrow.
As charge carriers, electrons and ions play the leading role in electrochemical energy storage devices and converters such as batteries and fuel cells. Proton...
Scientists from the Excellence Cluster Universe at the Ludwig-Maximilians-Universität Munich have establised "Cosmowebportal", a unique data centre for cosmological simulations located at the Leibniz Supercomputing Centre (LRZ) of the Bavarian Academy of Sciences. The complete results of a series of large hydrodynamical cosmological simulations are available, with data volumes typically exceeding several hundred terabytes. Scientists worldwide can interactively explore these complex simulations via a web interface and directly access the results.
With current telescopes, scientists can observe our Universe’s galaxies and galaxy clusters and their distribution along an invisible cosmic web. From the...
Temperature measurements possible even on the smallest scale / Molecular ruby for use in material sciences, biology, and medicine
Chemists at Johannes Gutenberg University Mainz (JGU) in cooperation with researchers of the German Federal Institute for Materials Research and Testing (BAM)...
19.06.2017 | Event News
13.06.2017 | Event News
13.06.2017 | Event News
28.06.2017 | Awards Funding
28.06.2017 | Earth Sciences
28.06.2017 | Physics and Astronomy