Research

Kindest cut makes virus programmable

Rice University lab modifies nanoscale virus to deliver peptide drugs to cells, tissues


0108_MOSAIC-1a-WEB
By Mike Williams | January 8, 2018

By chipping away at a viral protein, Rice University scientists have discovered a path toward virus-like, nanoscale devices that may be able to deliver drugs to cells.

The protein is one of three that make up the protective shell, called the capsid, of natural adeno-associated viruses (AAV). By making progressively smaller versions of the protein, the researchers made capsids with unique abilities and learned a great deal about AAV’s mechanisms.

The research appears in the American Chemical Society journal ACS Nano.

Rice bioengineer Junghae Suh studies the manipulation of nondisease-causing AAVs to deliver helpful cargoes like chemotherapy drugs. Her research has led to the development of viruses that can be triggered by light or by extracellular proteases associated with certain diseases.

AAVs are small — about 25 nanometers — and contain a single strand of DNA inside tough capsids that consist of a mosaic of proteins known as VP1, VP2 and VP3. AAVs have been used to deliver gene-therapy payloads, but nobody has figured out how AAV capsids physically reconfigure themselves when triggered by external stimuli, Suh said. That was the starting point for her lab.

“This virus has intrinsic peptide (small protein) domains hidden inside the capsid,” she said. “When the virus infects a cell, it senses the low pH and other endosomal factors, and these peptide domains pop out onto the surface of the virus capsid.

“This conformational change, which we termed an ‘activatable peptide display,’ is important for the virus because the externalized domains break down the endosomal membrane and allow the virus to escape into the cytoplasm,” Suh said. “In addition, nuclear localization sequences in those domains allow the virus to transit into the nucleus. We believed we could replace that functionality with something else.”

Suh and lead author and Rice graduate student Nicole Thadani think their mutant AAVs can become “biocomputing nanoparticles” that detect and process environmental inputs and produce controllable outputs. Modifying the capsid is the first step.

Of the three natural capsid proteins, only VP1 and VP2 can be triggered to expose their functional peptides, but neither can make a capsid on its own. Shorter VP3s can form capsids by themselves, but do not display peptides. In natural AAVs, VP3 proteins outnumber each of their compadres 10-to-1.

That limits the number of peptides that can be exposed, so Suh, Thadani and their co-authors set out to change the ratio. That led them to truncate VP2 and synthesize mosaic capsids with VP3, resulting in successful alteration of the number of exposed peptides. Based on previous research, they inserted a common hexahistidine tag that made it easy to monitor the surface display of the peptide region.

“We wanted to boost the protein’s activable property beyond what occurs in the native virus capsid,” Thadani said. “Rather than displaying just five copies of the peptide per capsid, now we may be able to display 20 or 30 and get more of the bioactivity that we want.”

They then made a truncated VP2 able to form a capsid on its own. “The results were quite surprising, and not obvious to us,” Suh said. “We chopped down that VP2 component enough to form what we call a homomeric capsid, where the entire capsid is made up of just that mutant subunit. That gave us viruses that appear to have peptide ‘brushes’ that are always on the surface.

“A viral structure like that has never been seen in nature,” she said. “We got a particle with this peptide brush, with loose ends everywhere. Now we want to know if we can use these loose ends to attach other things or carry out other functions.”

Homomeric AAVs display as many as 60 peptides, while mosaic AAVs could be programmed to respond to stimuli specific to particular cells or tissues and display a smaller desired number of peptides, the researchers said.

“Viruses have evolved to invade cells very effectively,” Suh said. “We want to use our virus as a nanoparticle platform to deliver protein- or peptide-based therapeutics more efficiently into cells. We want to harness what nature has already created, tweak it a little bit and use it for our purposes.”

Co-authors are Rice Ph.D. graduate Christopher Dempsey and alumna Julia Zhao and former lab manager Sonya Vasquez. Suh is an associate professor of bioengineering.

The research was supported by a National Science Foundation Graduate Research Fellowship to Thadani and a National Institutes of Health Nanobiology Interdisciplinary Graduate Training Program grant to Dempsey.




Social Posts

profile_image

Veterans Affairs

@DeptVetAffairs

At the Vietnam Memorial, a Lake Geneva Veteran bumps into a fellow Vet he hasn't seen in 48 years https://t.co/g1Cj0rXus9 via @620wtmj

39 mins ago
profile_image

U.S. Department of Veterans Affairs

VeteransAffairs

The jumps were intended to raise awareness of Operation Enduring Warrior, a veteran-founded nonprofit organization with programs to aid wounded military and law enforcement veterans with physical and emotional rehabilitation.

1 hour ago
profile_image

MD Anderson Cancer Center

@MDAndersonNews

“This study is proof of principle that we should keep going,” says our @JenniferLitton. #immunotherapy #bcsm #endcancer https://t.co/zUbvJvOqQF

1 hour ago
profile_image

University of Houston

@UHouston

RT @UHCougarFB: 📸 | The #HTownTakeover has arrived at Navy-Marine Corps Memorial Stadium. https://t.co/difmnpTYgt

1 hour ago
profile_image

Veterans Affairs

@DeptVetAffairs

Holocaust survivors visit museum with World War II Veterans https://t.co/JJOCvMt4U6 via @ABC7News

2 hours ago
profile_image

MD Anderson Cancer Center

@MDAndersonNews

Learn how an #immunotherapy clinical trial gave #melanoma survivor Karlee Steele a chance to help other patients. #endcancer https://t.co/6OCovaOl5N

2 hours ago
profile_image

Texas Children's

@TexasChildrens

A revolutionary treatment for allergies to peanuts and other foods is going mainstream—but do the benefits outweigh the risks? Learn more via @sciencemagazine: https://t.co/NopMMWUDha #texaschildrens

2 hours ago
profile_image

BCMHouston

@bcmhouston

Congratulations to the Dr. David Persse on receiving the American College of Emergency Physician's 2018 Outstanding Contribution to EMS award. https://t.co/olQqIQpndd

2 hours ago
profile_image

University of Houston

@UHouston

RT @UHpres: It needed a little editing! https://t.co/EC9HxN05NZ

3 hours ago
profile_image

Veterans Affairs

@DeptVetAffairs

West Virginia - More space to help counsel combat Veterans https://t.co/qPgeOFv4m5 via @WVVA

3 hours ago
profile_image

CHI St. Luke's Health

@CHI_StLukes

Join us for our FREE event featuring multiple #childbirth and newborn education classes, door prizes, and a #HospitalTour. Get your tickets today: https://t.co/b8skGCLUG6 https://t.co/njd8HFqHxn

4 hours ago
profile_image

University of Houston

@UHouston

RT @UHCougarFB: ICYMI: Here's what we're wearing...⚪ Helmet ⚪ Jersey 🔴 Pants#HTownTakeover https://t.co/ONWITFNeLT

4 hours ago
profile_image

BCMHouston

@bcmhouston

Curious about cochlear implants? Join the Center for Hearing and Balance for the 3rd annual Cochlear Implant Recipient and Candidate event on Oct. 23. https://t.co/B8n6K2BsnI

4 hours ago
profile_image

TAMU Health Sciences

@TAMHSC

Rural Pharmacies Are Closing: Where Does That Leave Patients? | Patient Advice | US News https://t.co/HWf3bSegta@usnews @tamhsc_cop @rchitexas #RuralHealth #Pharmacist #Pharmacy #HealthCare #TAMHSC #AggieHealth #TAMUHealth #PatientCare https://t.co/PEDTarbxA9

4 hours ago
profile_image

MD Anderson Cancer Center

@MDAndersonNews

#Cancer can be stressful. Find out how other survivors coped with stress and anxiety during treatment: https://t.co/WJb8aWh5z4 #endcancer https://t.co/F1sHd2NZbH

4 hours ago