Novel Drug That Prevents HIV From Developing Into Infectious Particle Discovered

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Highlights :

• Current HIV treatment targets viral enzymes but this has been plagued by drug resistance
• New capsid inhibitors that target viral protein shell (capsid) could be potential therapeutic option, while overcoming the issue of drug resistance as well
• HIV/AIDS has so far claimed nearly 35 million lives worldwide.

Novel "braking agent" that disrupts the development of the viral protein coat which is normally responsible for HIV infectivity, has been discovered by a group of scientists at the University of Delaware and the University of Pittsburgh School of Medicine

The findings of their work appear in Nature Communications in November 2017 and included an interdisciplinary research team from University of Delaware, the University of Pittsburgh School of Medicine, University of Illinois, National Cancer Institute, DFH Pharma and Vanderbilt University Medical Center.

Need of the Hour - Safe And Effective Antiretroviral Agents

For almost a decade from the mid-1990's to the mid 2000's, antiretroviral therapy (ART) has targeted viral enzymes. Although effective, resistance is emerging to these forms of treatment, especially with long term treatment. This has necessitated the search for newer and more effective treatment options. A major candidate for newer treatment target is the viral coat or capsid, an option that has not been explored until recently.

Looking at the Viral Dynamics to Identify Potential Treatment Target

In the quest for newer capsid inhibitor agents, the current team focused in great depth on studying the constantly changing viral dynamics during its early and late life cycle.

‘Newer anti-capsid agents such as Bevirimat could emerge as potential effective treatment options for AIDS overcoming the problem of drug resistance’

The motion of the virus molecules was estimated experimentally and simulated to about quadrillionths of a second-i.e. much faster than the flutter of a hummingbird's wings or blink of an eye.

"People used to be fixated on the static structures of viruses, but they are not rock solid," said

Tatyana Polenova, professor in UD's Department of Chemistry and Biochemistry. She is an expert in nuclear magnetic resonance (NMR) spectroscopy, which helps scientists identify and pinpoint the location of every atom in a structure and how each atom moves.

Although extremely challenging, Juan Perilla, who joined the UD faculty as an assistant professor this past June as a quantitative biophysicist, had created the earliest structural models of HIV as a postdoctoral scientist at the University of Illinois. Currently, at the University of Delaware, he regularly employs some of the world's largest supercomputers to create simulations of the various viral moving parts and study viral dynamics in the laboratory.

"Viruses like HIV and their constituent protein and nucleic acid molecules are dynamic entities that are constantly expanding and shrinking," Polenova added. "Their motions are like breathing."

Looking For Answers to a Long Unanswered Question

Using state of the art techniques, including solid-state and solution nuclear magnetic resonance (NMR) spectroscopy, high-end computer simulations, and cryo-electron microscopy (for which the Nobel Prize was awarded earlier this year) the research team analyzed the intricate protein structure of the virus during the various stages of its lifecycle.

This enabled them to get the answer to a long standing question namely how what happened in the final maturation stage of the virus where the immature non-infectious virion matured into a mature infectious viral particle.

Protein Structure of the Viral Capsid - What Changes Occur During Maturation

It is known that the HIV-1 Gag precursor protein is the master protein from which the protein blocks are separated off. The Gag precursor protein is structurally divided into four major domains: the N-terminal matrix (MA), the capsid (CA), the nucleocapsid (NC), and the C-terminal p6. Two spacer peptides are located between CA and NC (SP1) and between NC and p6 (SP2).

The findings of the team with regards to the protein structure alterations that take place during viral development were as follows

• The spacer peptide 1 (SP1), a key peptide has to be in a highly mobile structure to be cleaved by the virus protease, the enzyme that acts like a pair of scissors.
• In simulations, the peptide appears like a thin, thread like strand attached to corkscrews of curled ribbons that move constantly
• As soon as the SP1 peptide is cleaved, the HIV virus matures forming its protective shell and becomes transformed into an infectious particle.

"This peptide is always there in the final maturation step, but we were surprised that it is so disordered and dynamic," Polenova said.

Stopping this Final Step of Viral Maturation - Finding Newer Capsid Inhibitors

Seeking to prevent this final step in the virus life cycle that rendered it infectious, experiments at the University of Pittsburgh led by Angela Gronenborn, found the anti-HIV inhibitor Bevirimat interacted with the SPI peptide, thereby disrupting the development of the viral capsid "coat."

"We have to have a sense of these short-lived molecular fluctuations and processes of protein cleavage and capsid generation," Perilla said. "To add a new generation of capsid inhibitors to prevent HIV, you have to have very specific times and rates at which these drugs will work."

Preclinical drugs like Bevirimat (BVM) target the SP domain to inhibit the SP-NC cleavage and further research to elucidate the complex processes are needed. The outcome of future research in this direction may have major implications in the quest for new therapeutic strategies and novel drug targets for AIDS.

Importance of Interdisciplinary Collaboration and Teamwork

Perilla and Polenova acknowledge the importance of interdisciplinary teamwork involving individuals with expertise in techniques such as NMR and cryo-EM, and across the disciplines of virology, structural biology, biophysics, and biochemistry has been a key factor in the current study.

"This work would be impossible without our combined strength--I tell my students they need to learn to collaborate with people in other fields. Science is moving away from the single scientist being able to peer at things at atomic resolution," Polenova said. "It's no longer the situation of doing one thing as a single investigator. Now, we all come together."

References:

1. HIV-1 Capsid as a Target for Antiviral Therapy - (https:www.omicsonline.org/open-access/hiv1-capsid-as-a-target-for-antiviral-therapy-2155-6113-1000536.php?aid=66954)
2. Molecular Mechanisms of Retrovirus Infection - (http://www.ks.uiuc.edu/Research/HIV/)
3. Solid-state nuclear magnetic resonance - (https:en.wikipedia.org/wiki/Solid-state_nuclear_magnetic_resonance#Applications)

Source: Medindia

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