Drug design on HIV-1 protease

Drug design on HIV-1 protease


Although it receives little attention, AIDS continues to be a pandemic, with an estimated 35 million people infected as of 2014. Despite the increased awareness of AIDS worldwide, only about 54% of the population needing treatment have access to proper healthcare (as of 2012).

Once a person has been infected, the disease can be controlled but not eradicated, as the virus integrates itself into the human DNA, and treatment is therefore usually a life-long commitment. A large part of the at-risk population live in developing countries and this puts high demands on treatment costs, as well as maintaining a proper health infrastructure and increasing awareness.

A current and major threat is the development of drug resistance. HIV has the ability to rapidly change and adapt to specific drugs by introducing specific mutations. Several reports therefore highlight the importance of not slowing down the research but to continue the search for new, more potent and cheaper drugs against AIDS.

We are developing drugs against the enzyme HIV-1 protease, which is one of the three key enzymes that the virus carries and needs for replication. When a cell has been infected and starts to produce viral proteins in the form of one long peptide (pre-protein), the HIV-1 protease is needed to cut the peptide into the correct pieces, which can later fold and become functional new proteins. Without this process of the initial peptide, the viral proteins cannot form.

Several new inhibitors have been produced and tested to verify their potency as drugs. The inhibitors bind to the protease enzyme in a way that clearly reflects the binding of the peptide in the infected cells. This includes a variety of bonds that have to be preserved, both polar and non-polar, and the geometry of the inhibitor has to match the geometry of the binding site of the protease. The 3D structure of the protease and the ligand in complex is crucial in order to understand how the ligands bind and to design changes and modifications that may improve the binding. Therefore, the very intense X-ray beams of a modern synchrotron are needed to be able to build a full atomic model of the protease-inhibitor complex. With the invention of cheap and fast methods to synthesise the drugs and biochemical analysis, the structural studies at MAX IV Laboratory plays an important role to evaluate new inhibitors, test new variants and find ways to improve the binding and many other properties that a drug needs to possess.

This is a collaboration between staff at MAX IV Laboratory as part of the in-house research, Department of Medicinal Chemistry at Uppsala University, Medivir AB in Huddinge, University of Southampton, UK, and Tibotec, Belgium.


Johan Unge
Researcher at MAX IV Laboratory
+46 701 43 69 65