New ways to tackle cancer-causing virus, eye disease win CTSI funding awards
Friday, August 31, 2012
A promising new way to fight human herpes viruses and a drug delivery device to better treat a major cause of blindness have won development funding from UCSF’s Clinical and Translational Science Institute (CTSI).
The herpes virus treatment project, awarded $100,000 under CTSI’s T1 Translational Catalyst Awards, is led by Charles Craik, PhD, a faculty member in the UCSF School of Pharmacy’s Department of Pharmaceutical Chemistry. One of the project’s prime targets is the virus that causes the most common HIV/AIDS-associated cancer.
The development of the device to treat eye disease, which was awarded $85,000, is led by Tejal Desai, PhD, a faculty member in the Department of Bioengineering and Therapeutic Sciences, a joint department of the UCSF Schools of Pharmacy and Medicine.
The T1 Awards, which are offered twice a year, are designed to help drive promising early-stage research through the process of translating ideas into therapies that benefit patients. In addition to funding, they provide customized expert feedback and advice.
Finding protease inhibitors to fight diseases
For more than a decade, Craik has researched the basic science needed to treat the cancer-causing Kaposi’s sarcoma-associated herpes virus (KSHV), applying his particular expertise in protease enzymes, which play crucial roles in all organisms.
Indeed, Craik’s focus helped lead a UCSF team in the late 1980s to demonstrate that the selective inhibition of HIV’s protease enzymes would be an effective way of treating the virus. In the past two decades, pharmaceutical companies have developed protease inhibitors to treat HIV as well as Hepatitis C.
In nearly two dozen published studies identifying and analyzing the KSHV protease enzymes’ structure and function, Craik and colleagues have shown that the enzymes only become active when a pair of them (separately known as monomers) comes together. This combined enzyme, known as a dimer, then plays a vital role in the virus’ replication.
More recently, Craik’s lab discovered a small molecule dubbed dimer disrupter 2 (DD2) that binds to a site on the monomers’ interface, keeping them from changing their shape in a way that allows them to bind to their twins and activate. When a molecule binds to an alternative site on an enzyme and alters its activity, it is known as allosteric regulation.
In fact, all eight human herpes viruses, including those that cause diseases such as mononucleosis, shingles, and genital herpes, have dimeric proteases with interfaces that could be vulnerable to similar allosteric inhibition.
For example, a Craik-co-authored study found DD2 also inhibited the proteases in cytomegalovirus (CMV), a human herpes virus that can cause pneumonia, as well as serious inflammatory diseases of the eye, bowel, and brain in infants, transplant recipients, and other immunocompromised patients.
The drugs currently available to treat herpes virus infections are limited in effectiveness by increasing virus resistance or, especially in the case of CMV treatments, by severe side effects.
Aided by the new CTSI T1 funding, Craik and postdoctoral fellow Gregory Lee, PhD; biophysics graduate student Jonathan Gable; and fellow pharmaceutical chemistry faculty member Adam Renslo, PhD, will seek to modify the DD2 molecule. Their goals are to make it:
- a more potent inhibitor of KSHV and CMV proteases (so it could be effective at lower and thus safer drug concentrations).
- better able to cross cell membranes to reach the viruses.
They are also in the midst of screening more than 100,000 chemical compounds to seek even better herpes virus protease inhibitors, employing high-throughput automation at the School of Pharmacy’s Small Molecule Discovery Center. About 200 candidate molecules have already been identified for further analysis.
New nano-devices seek to save eyesight and money
Tejal Desai, PhD, is developing a much-needed thin-film device capable of delivering sustained doses of drugs to the back of the eye, where they can effectively treat the wet form of age-related macular degeneration (AMD). AMD causes loss of central vision due to abnormal blood vessel growth and leakage damaging the retina.
Eye drops are ineffective at reaching the back of the eye, thus many wet AMD patients are now treated via monthly drug injections into the eyeball. Daunting discomfort aside, the latter is neither pharmacologically optimal nor cost-efficient due to the drugs’ rapid breakdown and clearance from the body.
Desai’s devices will be as thin as a strand of hair with pores a mere 25 nanometers in diameter. Deployed into the back of the eye twice a year, they will deliver a sustained dose of drugs over time. It is estimated that the reduced number of treatments alone will save patients up to $15,000 per year.
The device’s development is supported by a four-year, $1.5 million grant from the National Eye Institute of the National Institutes of Health, but Desai notes that CTSI’s T1 funding “is really aimed at addressing some of the challenges related to scaling up and commercializing our technology.
“With the funds, we will be able to address the regulatory pathway and develop some processes for device manufacturing and quality control. These are critical issues not funded by traditional NIH grants.”
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