Benkovic Research Initiative

Patricia and Stephen Benkovic Research Initiative 

Benkovic Research Initiative – Call for Proposals  

Andrew Read:

Hello. I’m Andrew Read, director of the Huck Institutes of the Life Sciences at Penn State.

Phil Bevilacqua:

And I’m Philip Bevilacqua, Head of Penn State’s Chemistry Department in the Eberly College of Science.

Andrew Read:

It gives us great pleasure today to announce the launch of a new funding opportunity for Penn State researchers, focused on truly bold and pioneering work at the interface of chemistry and the life sciences.

Phil Bevilacqua:

This is the inaugural call-for-proposals for a brand new program – the Stephen and Patricia Benkovic Research Initiative.

Andrew Read:

Steve Benkovic is among the most celebrated and respected scientists in Penn State’s history.

Phil Bevilacqua:

And he’s also a living legend in the field of chemistry, which I can attest as a fellow chemist is the noblest of all the sciences. 

Andrew Read:

Well, as an evolutionary biologist, I find that statement debatable Phil. What is absolutely not debatable however, is how grateful we are to the Benkovic Family Foundation for their support in making this new program possible. 

Phil Bevilacqua:

The Benkovics believe – as do we – that breakthroughs in science happen when exceptional scientists have the freedom and resources to partner across disciplines in new and truly innovative ways. That’s why they’re making this investment in the Penn State research community to fund projects that are too risky, too innovative, to attract conventional funding.

Andrew Read:

That’s right, Phil. We can definitely agree there. But don’t take our word for it. Listen to the Benkovics themselves.

[MUSIC]

Stephen Benkovic:

As some of you know, Pat and I have worked together since we were married back in 1961. We share our lab’s accomplishments and today I will speak for both of us. 

You asked why Pat and I undertook this initiative. We both loved doing science. I certainly have. I’m still doing it, well past normal retirement age. The Benkovic Research Initiative is meant to fund risky but highly innovative research that has the potential for breakthrough discovery. I am well aware of the aversion of NIH and NSF study sections to fund such proposals. 

We were fortunate enough to have funds to test ideas that would not have been supported by conventional sources. With such money, I set up a corner of the lab to explore the use of Boron compounds in medicinal chemistry, despite having been told they would be far too toxic. 

The lab’s promising findings led to the founding of Anacor.  In a decade, Anacor had FDA approval for two drugs: Tavaborole and Euchrisa. On for nail fungus and the other for atopic dermatitis.  Anacor was then purchased by Pfizer and with a portion of those returns Pat and I established this initiative. 

Now it’s up to Penn State scientists to seize this opportunity and to do creative and inventive research. I hope they do.

[MUSIC]

Phil Bevilacqua:

Applications are open to all faculty at Penn State. Team proposals are welcome. We are interested in everything from basic science to translational work that is too early to attract venture capital.

Andrew Read:

In Year 1, the intention is to commit up to $1M across 2-4 projects, although exceptions could be made for truly outstanding proposals

Phil Bevilacqua:

Projects are expected to run for 1-3 years in the first instance. We hope to make this an annual call 

Andrew Read:

If you’ve got an idea too novel to attract all the usual funding agencies, we want to hear from you – and we want to hear from you fast.

Phil Bevilacqua:

Full proposals are due November 1st, but we want to hear your ideas well before that. 

Andrew Read:

And do keep in mind that we want really creative stuff here – this is not just a local substitute for an NIH R21 to generate pilot data. 

Phil Bevilacqua:

To read up on all the details – including all submission requirements and a list of more than a dozen examples of potential areas of research that would meet our criteria for support, check out our full RFP at the infoReady link in the description below this video. 

[MUSIC]

Stephen Benkovic:

I want to give other people the opportunity to do things a bit out of the ordinary. To maybe try something innovative and risky. I hope it pans out, but I hope at the same time they have great fun in trying to do it. How’s that? A little better?

Patricia Benkovic:

That was a little better

(Production crew cross-talk and laughter)

The Patricia and Stephen Benkovic Research Initiative is designed to support boldly innovative, high-risk proposals at the interface of chemistry and the life sciences that are too risky to attract traditional funding opportunities.

The program launched with an initial call for proposals in Fall 2021. The four projects below received first-round seed funding in Spring 2022.

Project 1:

Title: Targeting Cryptic Viral Epitopes for Pandemic Preparedness and Rapid Response through Integrative Cryo-EM and Mass Spectrometry

Researchers: Ganesh Anand, associate professor of chemistry, and biochemistry and molecular biology, Huck Institute of Life Sciences, Penn State

Susan Hafenstein, Huck Chair of Structural Virology; Professor of Biochemistry and Molecular Biology, Director of the Center for Structural Biology, Penn State

Neil Christensen, professor of pathology and laboratory medicine, and microbiology and immunology, Penn State

Concept: This work would integrate structural biology, chemistry, and immunology to fast-track target antivirals. The team’s approach offers a novel path for antiviral discovery that targets novel ‘weakest link’ virus epitopes, the part of the virus that is recognized by the immune system, for blocking viral entry into hosts. Preventing viral entry would stop infection early by preventing the virus from replicating within the host.

Risk: Skepticism among virologists regarding the use of linear viral epitopes as part of a targeted strategy for antivirals.  An integrated protocol to optimize the workflow is currently lacking.

Technical Details: During trafficking to find a suitable host, the protein shell of a virus stably encases genomic nucleic acid, but begins a precise disassembly process, under host-specific environmental conditions. A virus is at its most vulnerable when as it begins the disassembly process. The researchers seek to uncover novel epitopes associated with disassembly, that are critical for infection, but not apparent previously. Using amide hydrogen/deuterium exchange mass spectrometry (HDXMS) combined with cryo EM, the team will identify these epitopes, use them as targets, and rapidly generate antivirals. This combined technical approach will use poliovirus, the virus that causes the disease polio, as a model system and develop both biologics and small molecules as antivirals. The results will be validated by HDXMS, proteomics and cryo EM.

Once a “map” of the structural changes of the virus has been created and targets for novel treatments have been identified, it could be extended to other RNA viruses. This combination of dynamics measurements by structural mass spectrometry and atomic resolution cryo EM structures has not been done before and is more powerful than either approach alone.

Potential Application: This project could bring support to the global eradication of poliovirus and allow the development of preemptive antiviral libraries against RNA viral targets. The creation of these antiviral libraries could lead to rapid response in the event of future outbreaks and advance future RNA virus pandemic preparedness.

Project 2

Title: Development of Antibiotic Adjuvants to Avert Resistance Conferred by Radical S-adenosylmethionine-dependent Methyltransferases

Researchers:

Squire J. Booker, Evan Pugh University Professor of Chemistry and of Biochemistry and Molecular Biology, Penn State University

John N. Alumasa, Associate Research Professor of Biochemistry and Molecular Biology, Penn State University

Olga A. Esakova, Assistant Research Professor of Chemistry, Penn State University

Concept: Bacteria have evolved to develop countermeasures for antibiotic action that lead to antibiotic resistance. Some strains of methicillin resistant Staphylococcus aureus (MRSA) possess plasmids, genetic structures that can replicate independently, containing a chloramphenicol–florfenicol resistance gene (cfr). The cfr is a gene associated with antibiotic resistance and encodes a radical S-adenosylmethionine-dependent methylase (RSMT). Strains possessing this gene have developed multi-drug resistance to five major classes of antibiotics. RSMTs perform a variety of reactions within bacteria, and some bacteria take advantage of the activity of RMSTs to reinforce their defenses against antibiotics, presenting a potential therapeutic target. Inhibiting this activity would not likely elicit a response in the bacteria as Cfr is not essential for the bacteria’s survival; however, it would prevent the bacteria from developing resistance to associated antibiotics it may encounter. A treatment that targets Cfr in MRSA could be used in combination with antibiotic therapy to prevent these bacteria from becoming resistant.

Technical Details: The team will use a combination of crystallographic and computer-aided drug discovery techniques to identify key structural elements of compounds that bind to the active site of bacterial ribosomal RNA methylases. The information gathered from these studies could be used as a building block to facilitate the design of new compounds that selectively inhibit the enzymatic activity of radical S-adenosylmethionine-dependent methylases. 

Risk: There is a possibility of severe mammalian cell damage with the competitive inhibitors of SAM. Previous attempts to crystallize MRSA Cfr have failed.

Potential Application: Identified inhibitors of Cfr activity could help to avoid the onset of resistance in pathogenic strains of bacteria, establishing new strategies for combating multidrug-resistant superbugs like MRSA. Furthermore, these compounds could be administered in combination with antibiotics that were once unsuitable based on their inactivity towards Cfr-mediated resistance, facilitating the treatment of infections caused by bacterial strains carrying this gene.

Project 3

Title: Nanoengineered Biomaterials to Prevent or Reverse Antimicrobial Resistance

Researcher: Amir Sheikhi, assistant professor of chemical engineering and biomedical engineering (by courtesy)

Risk: This work was considered too risky in the complete absence of any anti-antibiotic candidate compounds. 

Concept: Antibiotics are valuable drugs because they directly attack bacteria, but in doing so, they create the conditions that favor the evolution of antibiotic-resistant bacteria. Resistance ultimately occurs for almost every antibiotic. Sheikhi will target natural selection itself, to break the connection between antibiotic use and antibiotic resistance.  

Technical Details: Researchers led by Sheikhi in the Bio-Soft Materials Laboratory (B-SMaL, www.sheikhilab.com) aims to create biomimetic anti-antibiotic compounds that would be used in tandem with antibiotic treatment. The antibiotics would treat the bacterial infection, and the anti-antibiotics would prevent antimicrobial resistance.

The research team will focus on clinically relevant antibiotics in their study. These antibiotics are often used to combat infection in the blood, but the antibiotic then makes its way into the gastrointestinal (GI) tract, where it continues to attack bacteria. Many bacteria in the GI tract are Colonizing Opportunistic Pathogens (COPs); these are the sources of fecal-oral transmission and the primary source of transmission in healthcare settings. COPs can develop resistance to the antibiotic while in the host's gut. The resistant bacterial strain is then passed on to the next host, and the antibiotics usually used to treat this infection would not work. 

The team aims to develop anti-antibiotic biomaterials that inhibit the antibiotics from attacking other bacteria. The team will directly test this theory in vitro. Future in vivo assessments will be conducted in collaboration with Andrew Read, director of the Huck.

Potential Application: As a therapy used in tandem with primary antibiotic treatment, anti-antibiotic biomaterials will potentially protect the partner antibiotic from resistance. This solution could also reverse antibiotic resistance. 

Project 4

Title: Novel Methods for Non-invasive Neuropeptide Administration to the Brain

Researchers:

Nikki Crowley, assistant professor of biology and biomedical engineering, Penn State

Scott Medina, assistant professor of biomedical engineering, Penn State

Concept: Neuropeptides, signaling molecules found in the brain, are promising therapies for brain disorders such as depression, addiction, and brain cancers. However, effectively delivering these peptides to the brain requires getting them across the blood-brain barrier. Right now, such treatments often do not make it across this barrier, causing side effects in other areas of the body.

Crowley and Medina's project, with collaboration between engineering, acoustics, and neuroscience, aims to overcome technological and biochemical issues in crossing the blood-brain barrier that could lead to new, non-invasive precision drug delivery strategies to the brain.

RiskComplete absence of evidence this will solve the transport problem; risk of off-target effects. 

Technical Details: The team will prove their concept by creating a nanoemulsion loaded with neuropeptide cargo and delivering it to targeted regions of the brain in an animal model. A nanoemulsion is a nano-sized (from 10 – 1,000 nm) droplet that is stabilized using surfactants. Aided by ultrasound, the neuropeptides will be delivered across the blood-brain barrier to affect their brain targets and cause a change in neuronal signaling. 

The blood-brain barrier will be opened with millimeter precision by bursting the nanoemulsions at the blood-brain barrier using a miniaturized ultrasound imaging device; directly delivering the peptide across these transient openings to a specific area of the brain.

The effectiveness of the peptide administration will be confirmed by the observation of the expected changes in neuronal signaling caused by the peptides and the integrity of blood brain barrier will be monitored using advanced electrophysiology and imaging methods. The team should also observe a change in behavior in multiple animal models.

Potential Application: This project could transform drug administration to targets in the brain while limiting the effects of these treatments on the body without compromising the blood brain barrier. This technique could allow for more significant treatment efficacy with fewer side effects for many brain-related disorders.