Duo to study anti-HIV mechanism

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BIRMINGHAM, Ala.—Trana Discovery, announced last week that its recently-developed HIV high-throughput screening assay designed to identify compounds that inhibit the use of transfer RNA (tRNA) by HIV has the ability to select compounds with anti-HIV bioactivity. Because tRNA is essential for HIV replication, disruption of the virus's ability to use tRNA appears to represent a novel target for anti-HIV therapy. In a recent live cell-based study, a subset of compounds identified using the new Trana HIV 201 assay proved to inhibit the HIV virus through a mechanism other than inhibition of reverse transcriptase. The study was conducted in collaboration with and by Southern Research Institute.
CARY, N.C. – Trana Discovery Inc. and Southern Research Institute have announced a collaborative research agreement that could lead to the discovery of new classes of drugs for the treatment of patients infected with HIV. Under the agreement, Trana will screen Southern Research's library of approximately 1000 nucleosides against its unique, patented probes to identify anti-infectives with a novel mechanism of action.
The Trana probes are employed in a high-throughput screening process to identify compounds that possess tRNA inhibitory activity. By inhibiting the role of tRNA and crippling protein assembly, protein synthesis cannot proceed, thus stopping pathogen growth and the spread of infection. Most pathogens responsible for causing infectious diseases—including HIV, the virus that causes AIDS—require tRNA for replication.
"Most anti-infectives deal with ribosome or cell wall synthesis inhibition," notes Steve Peterson, CEO of Trana Discovery. "No one has looked at tRNA as an entire molecule."
In HIV studies, Trana is looking a specific step where it is known that intervention is possible as HIV enters the cell and is integrated into a new viron that then reenters the cytoplasm to continue infecting other cells. The Trana assay identifies inhibitors of the tRNA recruited by HIV during this phase of replication.
"Step 8 is where the virus must go into a cell, typically a T-cell, to recruit a tRNA lysine," Trana's Peterson says. "Other researchers have demonstrated that where tRNA lysine has been physically removed, HIV won't reproduce. HIV takes human tRNA and unfolds it into a non-human shape, but the anticodon stem loop (Step 8) is still there. We are looking for compounds that bind to it and, in effect, remove the key from the lock so it cannot be opened to reproduce."
Trana's technology can also be used to interrupt the life cycle of bacteria and fungal pathogens. The company's business model is to license its technology and intellectual property for specific viruses, bacteria and fungi so that licensees' libraries can be used to develop multiple drugs.
Southern Research is a leader in the field of nucleoside chemistry and biology. To date, the institute has discovered six FDA-approved cancer drugs and has four additional drugs that are currently in clinical trials. SRI claims that no other company or institution has brought six of its own cancer drug discoveries to market.
"There are unique components to the formula here that are necessary for drug discovery," says David Harris, director of drug discovery business development at Southern Research. "We have a full tool box – from early to late, enough scale to make it through to IND, a clear focus on the goal of drug discovery and the freedom to pursue our goals that is very similar to that found in academia."
The institute initiated a program two years ago to expand its biological and chemical diversity through external collaborations.
"We have been looking to screen our proprietary repository against new targets to identify compounds that deserve further investigation," Harris adds. "We're particularly excited about the possibility of discovering a new class of anti-HIV medicine through the use of the tRNA mechanism of action."
"We have been seeking compounds to demonstrate commercialization opportunities for our tRNA intellectual property and for further chemical optimization," adds Peterson. "This agreement is a great step toward the advancement of our technology."
In the future, the partners plan to explore a variety of joint projects to discover new compounds for the treatment of other serious bacterial and viral infectious diseases.

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