Ian W. Windsor 

Ian W. Windsor

Degree Program: Biochemistry
Faculty Supervisor: Ronald Raines
Phone: (608) 262-3040
Email iwindsor@wisc.edu

Current Research

Human immunodeficiency virus (HIV) is the causative agent of acquired immunodeficiency syndrome (AIDS). Nearly 33.3 million people are infected with HIV resulting in 1.8 million deaths each year. Vaccine attempts appear to be futile due to the rapid rate of evolution of the virus which allows the virus to evade recognition by the adaptive immune system. Current HIV treatment strategies involve a cocktail of drugs that inhibit several enzymes in the HIV lifecycle called highly active antiretroviral therapy (HAART). Likewise due to the high mutation rate of HIV, resistance develops as mutations are selected for which maintain enzymatic function, yet reduce affinity for inhibitors. There is a strong impetus to develop therapeutic strategies that are not susceptible to resistance. We propose two such strategies. First, we propose developing covalent inhibitors of HIV protease using boronic acids. Covalent modification of the enzyme will decrease the dissociation rate of inhibitors and substituting a hydrogen bond donor with a boronic acid can achieve this effect. Second, we are continuing to develop cytotoxins that are specific to HIV infected cells. Inspired by digestive zymogens, the Raines lab has created zymogen Ribonucleases. Circular permutation of the Ribonuclease was used to install a linker over the active site. This linker sterically occludes the substrate from binding and contains a sequence that is recognized by HIV protease. This approach generated a Ribonuclease that had a 50-fold increase in activity and near wild-type activity upon proteolysis. We will improve this design by using inteins to make a circular protein. We will also introduce strain in the active site by using a shorter linker that will distort the proximal active site residues.

Abstract (PDF)

Resume (PDF)

 

 

 


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