New approach in chemical biology aims to decrease drug resistance  

November 21, 2006 

WORCESTER, MA-Treatment of viral infections like HIV is particularly challenging. Because viruses such as HIV can change their protein coats rapidly, over time they become less recognizable to drugs, which must be able to find their protein targets reliably in order to be effective. In "Discovery of HIV-1 Protease Inhibitors with Picomolar Affinities Incorporating N-Aryl-oxazolidinone-5-carboxamides as Novel P2 Ligands," published November 14 in an early online edition of the Journal of Medicinal Chemistry, University of Massachusetts Medical School Professor of Biochemistry & Molecular Pharmacology Tariq M. Rana, PhD, and Associate Professor of Biochemistry & Molecular Pharmacology Celia A. Schiffer, PhD, and colleagues, report impressive new findings that identify an intriguing target area in HIV and describe the synthesis and biological evaluation of a novel series of HIV-1 protease inhibitors. 

HIV-1 protease plays a critical role in the virus life cycle and is essential for viral maturation. Inhibition of HIV-1 protease leads to the production of noninfectious virus particles and is a promising therapeutic target for antiviral therapy in AIDS patients. In fact, HIV-1 protease inhibitors represent the most potent anti-AIDS drugs reported to date and are essential components of highly active antiretroviral therapy. 

While anti-AIDS chemotherapy based on HIV-1 protease has been remarkably successful in decreasing mortality, the emergence of mutations of HIV-1 that are resistant to current drug regimens is a critical factor in the clinical failure of antiviral therapy. For most of the currently approved protease inhibitors, the emergence of multidrug-resistant (MDR) protease variants poses a great challenge to the efficacy of these drugs. Therefore, the development of the next-generation HIV-1 protease inhibitors has been the focus of intense research efforts in recent years as there is an increasing need to discover new classes of protease inhibitors that are less susceptible to drug resistance. 

In this research, Drs. Rana, Schiffer and colleagues employ a new strategy to reduce the probability of drug resistance, expanding upon previous studies published in 2004, where Schiffer and colleagues were able to determine the crystal structures of many HIV protease target substrates to compare their shape with existing protease inhibitors. An understanding of this shape is particularly important, as it explains how the protease recognizes substrates within its binding site. Significantly, the investigators found that some of the inhibitor's binding area protruded beyond that of the substrates, and many mutations that cause drug resistance occur at these locations.  Drug resistance occurs since mutations at these positions do not allow inhibitors to bind but allow substrates to continue to be recognized and cut by the HIV protease. 

To correct for this binding area protrusion-rather than targeting a particular amino acid sequence (the target for the majority of currently improved inhibitors)-the investigators designed inhibitors targeting an area of the viral protease which is necessary to recognize its substrate.  Confirming the validity of this strategy, the Rana lab synthesized and biologically evaluated a novel series of highly potent HIV-1 protease inhibitors.  To understand the mechanism of inhibition by these protease inhibitors, the Schiffer lab analyzed the crystal structures of the two most potent inhibitors in complex with the HIV-1 protease, providing significant new insight into the future design of novel inhibitors.  Thus, developing other drugs that target these regions of HIV-1 protease may be more promising for the creation of long term treatments less likely to cause drug resistance.  

About The University of Massachusetts Medical School 
The University of Massachusetts Medical School is one of the fastest growing medical schools in the country, attracting more than $174 million in research funding annually.   A perennial top finisher in the annual U.S.News & World Report ranking of primary care medical schools, UMMS comprises a medical school, graduate school of nursing, graduate school of biomedical sciences and an active research enterprise, and is a leader in health sciences education, research and public service.

Kelly Bishop