The World Health Organization estimates that 34 million people are currently living with HIV worldwide. Approximately 1.8 million people died from AIDS this past year, placing the total number of deaths from the AIDS epidemic at more than 30 million since the disease was first recognized in 1981 (www.unaids.org). Current drug treatments for individuals infected with HIV have dramatically increased the life expectancy of HIV positive patients. Unfortunately, prolonged exposure to HIV drugs can present additional health problems and complications. It is imperative that new HIV drug targets are explored and understood until a cure for HIV is discovered. My research focuses on understanding the fundamental mechanisms of a new class of HIV drugs and drug targets.
Highly Active Antiretroviral Therapy (HAART) is the current treatment of HIV, which includes a mixture of drugs that target specific parts of the HIV virus. The HAART treatment has been shown to suppress HIV replication to below the limits of detection and consequently slows the progression of AIDS and AIDS-related mortality. Unfortunately, side effects from the HAART treatments undermine its effectiveness. In addition, although HAART greatly reduces HIV replication, it does not completely halt it, and treatment must continue throughout the patient’s lifetime. Long-term exposure to the drugs increases the possibility of both related harmful side effects, such as progressive liver disease, and the occurrence of drug-resistant HIV strains. A patient is required to take 90 to 95 percent of the recommended drug dose to achieve long-term undetectable HIV levels. Any lower level dosage of the drugs greatly reduces the suppression of the virus and enhances HIV mutations. Viral-resistant strains of HIV can complicate treatment, especially if newly infected individuals contract the drug-resistant HIV strains. All of these problems, as well as others, lead to treatment failure rates of as high as 44 percent in patients infected with HIV.
The AIDS epidemic has created an urgent need for the development of new HIV drug candidates, which necessitates an understanding of the fundamental binding characteristics of current and developmental HIV drugs. The entry of HIV into a human cell involves the interaction of several proteins, each of which may serve as potential targets for inhibitory drugs. Most interest has been centered on the exterior of HIV, which is made up of a protein complex known as the envelope spike. This outer portion of HIV mediates how HIV first contacts, then enters the human host cell. A small drug with the capability of interfering with the envelope spike can potentially prevent HIV from entering the human cell, thus preventing the spread of the virus within the infected human’s body. These drugs are commonly referred to as HIV viral entry inhibitors.
In 2003, the pharmaceutical company Bristol-Myers Squibb developed a small molecule HIV viral entry inhibitor drug known as BMS-378806 (BMS-806). This drug became an attractive target as a potential antiviral drug and as a probe to study HIV entry, as it is a small molecule that could be taken orally. BMS-806 was identified by screening millions of compounds and was found to be a potent inhibitor of HIV entering human cells. The specific mechanism of how the drug actually works is still not understood. Consequently, a systematic study of BMS-806 may provide substantial insight toward both the mechanism of binding to the envelope spike of HIV and the development of related HIV inhibitors.
Nazareth students in my research group are focusing on two aspects of BMS-806. The first entails the chemical synthesis of BMS-806 derivatives to determine what functionality allows the drug to prevent HIV from entering human cells. This is achieved by methodically removing functional groups from BMS-806 utilizing synthetic organic chemistry, then sending the newly synthesized drug to our collaborator, Dr. Ernesto Freire’s group in the Department of Biology at Johns Hopkins University, to verify if the drug still works. If removing a functional group results in loss of BMS-806 potency, then that functional group is a key component. On the other hand, if a functional group is removed and the drug maintains its inhibition properties, then that functional group could either be eliminated or improved upon to enhance the drug. These experiments allow us to understand how the drug works and give us the opportunity to improve the drug’s binding capabilities.
The second aspect of our research involves chemically attaching a synthetic linker to BMS-806 with the intent of creating a medical diagnostic device. Right now, all of the HAART small molecule drugs target the inside of the HIV virus. BMS-806 is the first small molecule drug that attaches to the outer membrane of the virus. We can use the binding proper- ties of BMS-806 to our advantage by attaching one end of a synthetic linker to BMS-806 and the other to an optically active surface, such as a porous silicon chip. Our collaborator, Dr. Lisa DeLouise in the Department of Dermatology at the University of Rochester Medical Center, has demonstrated using porous silicon chips in the detection of opiates and their metabolites in urine samples. Using similar methodology to the detections of opiates, we can potentially detect the proteins on the outer membrane of HIV with the modified BMS-806 drug. The porous silicon chip technology could allow for an immediate and label- free detection of HIV as opposed to waiting several days for blood samples to be analyzed.
The lifespan of an individual infected with HIV has significantly increased since the early 1980s, when a positive HIV test was widely considered a death sentence. However, the number of individuals infected with HIV continues to increase, and new therapies are always needed. Our research is intended to increase the knowledge of how HIV viral entry inhibition works. In doing so, an entire new class of HIV drug therapy can potentially alleviate many of the current HAART drug resistance and HIV mutation concerns. In addition, the knowledge gained from understanding how small molecule drugs like BMS-806 attach to the outer membrane of HIV can lead to faster and cheaper methods of HIV detection. Through earlier detection, combined with additional treatment options, we can only hope to decrease the HAART failure rate and continue to prolong the lives of individuals infected with HIV.
Stephen Tajc, Ph.D., is assistant professor in chemistry and biochemistry.