First-ever covalent irreversible inhibition of a protease central to hepatitis C infection

November 28, 2010

Avila Therapeutics, Inc., a biotechnology company developing novel targeted covalent drugs, has published research in Nature Chemical Biology demonstrating the first-ever selective irreversible inhibition of a viral protease using a targeted covalent drug. In the paper titled "Selective Irreversible Inhibition of a Protease by Targeting a Non-Catalytic Cysteine", Avila used its proprietary Avilomics platform to design covalent irreversible protease inhibitors that are highly selective, potent and with superior duration of action as compared to conventional protease inhibitors.

Importantly, the published research demonstrates that covalent drugs can be designed and targeted to irreversibly and covalently bond to molecular domains specific to proteases. This is the first report of the irreversible covalent approach being successfully extended to proteases, a very broad class of proteins that includes many important potential drug targets.

"This research elevates covalent drug design to a fundamentally new level," said Simon Campbell, PhD, CBE, FMedSci, FRS, a renowned scientist and former Senior Vice President for Worldwide Drug Discovery and Medicinal R&D Europe of Pfizer. "By creating extremely selective protease inhibitors with their platform, Avila is showing the remarkable therapeutic potential of irreversible covalent drugs to address a broad spectrum of drug targets."

"This publication showcases the creation of a whole new class of small molecule drugs," said Juswinder Singh, PhD, Chief Scientific Officer of Avila and a co-author of the paper. "This approach can make a difference to patients living with HCV infection, and we expect to make an impact in other important areas such as cancer and inflammatory disease."

In order to maximize selectivity and minimize off-target effects, the irreversible covalent inhibitors of HCV protease were designed to covalently target a unique structure in the HCV protease not found in human proteases. Key findings include:

  • A representative irreversible covalent inhibitor designed, by Avila, was shown to inhibit the HCV protease (also known as "NS3") in cells at a concentration of 6 nM .
  • Specific covalent bond formation between the drug and target protease was demonstrated through use of mass spectrometry and also x-ray crystallography.
  • Very high selectivity of the Avila compounds was demonstrated by showing no notable inhibition of a panel of human proteases in biochemical assays with additional specificity demonstrated in cellular assays; this was contrasted experimentally with Telaprevir, an HCV protease inhibitor in late-stage clinical testing which demonstrated off-target biochemical activity against several human targets.
Avila has subsequently optimized additional drug candidates, yielding current development candidates, AVL-181 and AVL-192, which have excellent pharmacokinetics and bind potently to wild- type HCV protease as well as multiple genotypes and mutant forms of HCV .

Explore further: Metal-containing compounds show promise as HIV weapon

Related Stories

Metal-containing compounds show promise as HIV weapon

October 31, 2005

A molecule consisting of two "cages" of metallic atoms bound to carbon has shown great promise in preliminary tests of becoming a new weapon in the anti-HIV arsenal, researchers at UT Southwestern Medical Center report. The ...

Hepatitis C virus enzyme sites revealed

July 24, 2006

U.S. researchers say the crystal structure of one of the hepatitis C viral proteins might offer new opportunities for antiviral drug design.

Anti-HIV drugs reduce the cause of some forms of vision loss

May 23, 2008

A potential new therapeutic use for anti-HIV drugs known as protease inhibitors has been suggested by a team of researchers from Harvard Medical School, Boston, and Inserm U848, France, as a result of their work in a mouse ...

Researchers identify new drug target for Kaposi's sarcoma

July 30, 2009

UCSF researchers have identified a new potential drug target for the herpes virus that causes Kaposi's sarcoma, re-opening the possibility of using the class of drugs called protease inhibitors against the full herpes family ...

Putting the brakes on drug-resistant HIV

September 17, 2010

(PhysOrg.com) -- HIV-1 protease inhibitors were added as a component of highly active antiretroviral therapy (HAART) in the mid-1990s, and have played a key role in that treatment regimen ever since. However, the emergence ...

Recommended for you

Findings illuminate animal evolution in protein function

July 27, 2015

Virginia Commonwealth University and University of Richmond researchers recently teamed up to explore the inner workings of cells and shed light on the 400–600 million years of evolution between humans and early animals ...

New polymer able to store energy at higher temperatures

July 30, 2015

(Phys.org)—A team of researchers at the Pennsylvania State University has created a new polymer that is able to store energy at higher temperatures than conventional polymers without breaking down. In their paper published ...

How to look for a few good catalysts

July 30, 2015

Two key physical phenomena take place at the surfaces of materials: catalysis and wetting. A catalyst enhances the rate of chemical reactions; wetting refers to how liquids spread across a surface.

Yarn from slaughterhouse waste

July 29, 2015

ETH researchers have developed a yarn from ordinary gelatine that has good qualities similar to those of merino wool fibers. Now they are working on making the yarn even more water resistant.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.