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!
Researchers release the brakes on the immune system
18.10.2017 | Rheinische Friedrich-Wilhelms-Universität Bonn
Norovirus evades immune system by hiding out in rare gut cells
12.10.2017 | University of Pennsylvania School of Medicine
University of Maryland researchers contribute to historic detection of gravitational waves and light created by event
On August 17, 2017, at 12:41:04 UTC, scientists made the first direct observation of a merger between two neutron stars--the dense, collapsed cores that remain...
Seven new papers describe the first-ever detection of light from a gravitational wave source. The event, caused by two neutron stars colliding and merging together, was dubbed GW170817 because it sent ripples through space-time that reached Earth on 2017 August 17. Around the world, hundreds of excited astronomers mobilized quickly and were able to observe the event using numerous telescopes, providing a wealth of new data.
Previous detections of gravitational waves have all involved the merger of two black holes, a feat that won the 2017 Nobel Prize in Physics earlier this month....
Material defects in end products can quickly result in failures in many areas of industry, and have a massive impact on the safe use of their products. This is why, in the field of quality assurance, intelligent, nondestructive sensor systems play a key role. They allow testing components and parts in a rapid and cost-efficient manner without destroying the actual product or changing its surface. Experts from the Fraunhofer IZFP in Saarbrücken will be presenting two exhibits at the Blechexpo in Stuttgart from 7–10 November 2017 that allow fast, reliable, and automated characterization of materials and detection of defects (Hall 5, Booth 5306).
When quality testing uses time-consuming destructive test methods, it can result in enormous costs due to damaging or destroying the products. And given that...
Using a new cooling technique MPQ scientists succeed at observing collisions in a dense beam of cold and slow dipolar molecules.
How do chemical reactions proceed at extremely low temperatures? The answer requires the investigation of molecular samples that are cold, dense, and slow at...
Scientists from the Max Planck Institute of Quantum Optics, using high precision laser spectroscopy of atomic hydrogen, confirm the surprisingly small value of the proton radius determined from muonic hydrogen.
It was one of the breakthroughs of the year 2010: Laser spectroscopy of muonic hydrogen resulted in a value for the proton charge radius that was significantly...
17.10.2017 | Event News
10.10.2017 | Event News
10.10.2017 | Event News
20.10.2017 | Information Technology
20.10.2017 | Materials Sciences
20.10.2017 | Interdisciplinary Research