Researchers from UMich release fresh study on a chemical molecule that may be used to cure HIV.

University of Michigan researchers recently reported fresh findings on a chemical molecule that may one day be used to treat HIV. The research details a collaborative effort by the Collins and Sherman labs to alter concanamycin A, a chemical substance produced by bacteria, which may potentially lead to an HIV cure. It was published in the Journal of Medicinal Chemistry on March 7.

HIV attacks white blood cells, which are responsible for fighting infections in the body, weakening the immune system. The body becomes more vulnerable to diseases like tuberculosis and pneumocystis pneumonia, as well as cancers like lymphoma, Kaposi sarcoma, and cancers linked to the human papillomavirus, when the number of white blood cells declines. HIV turns into AIDS if the white blood cell count is less than 200 cells per microliter of blood.

Because HIV can hide from killer cells that typically eradicate viruses, the Nef protein prevents the immune system from identifying the virus's presence. Kathleen Collins, a professor of microbiology and immunology at the University of Michigan and one of the study's co-authors, has spent more than 20 years researching the Nef protein. Collins stated that in order to quantify the amounts of MHC class I molecules and identify compounds that counteract the effects of Nef, her lab created a molecular screening method known as high-throughput screening.

"At the Chemical Genomics core facility at the Life Sciences Institute here at the University of Michigan, we screened a lot of small molecule libraries that were available," said Collins. "After screening hundreds of millions of molecules, we were unable to locate any that would stop the specific Nef activity that we were interested in. The facility's director then recommended that we take a closer look at a few novel compounds that David Sherman's research team extracts from the ocean.

Over the past two decades, David Sherman, a research professor at the University of Michigan Life Sciences Institute, has amassed a sample library of over fifty thousand microbial natural product extracts from marine microorganisms. Collins searched the library for a match that might counteract Nef's effects and eventually settled on a substance called bafilomycin, which is made by a Papua New Guinean bacterium.

Sherman stated, "We already knew there was a larger family of this class of natural products called pleco macrolide when we found out it was bafilomycin." We began screening some of them because they are offered for purchase. We would buy a tiny quantity, just enough to test them, and it turned out that concanamycin A was the most effective.

Sherman stated that the cost of CMA could be close to $1,000 per milligram. A wild-type strain of bacteria that produced one milligram of CMA per liter was given to him by a colleague; however, the reactions used in the research required at least thirty milligrams of the molecule. Utilizing genetic engineering to enhance CMA synthesis and modifying the bacterial environment, Filipa Pereira, a senior member of the Sherman Lab and research investigator at the Life Sciences Institute, was able to achieve a 2,000-fold increase in concanamycin A production.

The fact that CMA inhibits a cellular protein called vacuolar ATPase, which is crucial for protein turnover, is a barrier to the development of anti-HIV drugs. Proteins must be broken down by the lysosome, which depends on V-ATPase, when they deteriorate or age. Collins stated that the goal of her lab's work was to produce CMA variants that would inhibit Nef more strongly while having less of an impact on V-ATPase.

Collins stated, "We wanted to make sure that we reduced any possible toxicity if we were thinking about using it in people as a treatment... because it also has activity against a cellular protein called Vacuolar ATPase." "Although the primary inhibitory effect on (V-ATPase) is observed at elevated doses, we aimed to maximize the size of our safety window. Thus, in collaboration with David, we altered the CMA molecule so that it could be separated from bacteria.

The only way to keep HIV at low levels in the body is to prevent the virus from growing, as there is currently no known cure for the infection. The estimated monthly cost of therapy ranges from $1,800 to $4,500. Patients are required to take an HIV treatment pill daily or have an HIV treatment shot every one to two months for the duration of their lives. The Pre-Pharmacy Student Organization's social events coordinator, Lauren Cupchak, a College of Pharmacy student, stated that individuals on lifetime HIV therapy would be greatly impacted by a cure.