Hepatitis C:HCV Protease AVL-192/Avilomics platform to covalent irreversible protease inhibitors

Irreversible inhibition of a protease central to hepatitis C infection; New HCV Protease AVL-192:

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Also See: Avila Presents Data On Their Hepatitis C Drug AVL-192 At AASLD
Dec - New Protease blockers that irreversibly inhibit the HCV protease enzyme

Mon, Nov 29, 2010

A new study has demonstrated that irreversible covalent inhibition can increase selectivity, potency and duration of action, broadens applications for targeted covalent drugs to the protease gene family.

Avila Therapeutics Inc., a biotechnology company developing novel targeted covalent drugs, has demonstrated the first-ever selective irreversible inhibition of a viral protease using a targeted covalent drug.

Avila has 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.

The research has demonstrated that covalent drugs can be designed and targeted to irreversibly and covalently bond to molecular domains specific to proteases.

"This research elevates covalent drug design to a fundamentally new level. 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," said Simon Campbell , a renowned scientist.

"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," said said Juswinder Singh, co-author of the paper.

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.

The findings were published in the journal Nature Chemical Biology. (ANI)

Avila Presents New Data on its Novel, Orally-Available Targeted Covalent Drug, AVL-192

Covalent Inhibition Achieves Superior Potency Against Drug-Resistant HCV Mutants
http://www.natap.org/2010/HCV/112910_01.htm

Press Release From Avila

Hepatitis C: Avilomics™ platform to design covalent irreversible protease inhibitors

"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".

WALTHAM, MA – 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 protease

New Protease blockers that irreversibly inhibit the HCV protease enzyme

Sticking Fast To Foil Hepatitis C

Carmen Drahl

Biochemistry:

Aiming beyond the active site of a virus's key protease yields selective blockers

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Hanging Tough A covalent inhibitor (blue) binds irreversibly to a cysteine in the substrate-binding site of hepatitis C protease (green). The active site serine is shown in red.

By targeting a noncatalytic cysteine, researchers have designed selective irreversible blockers of a protease enzyme essential for hepatitis C virus replication (Nat. Chem. Biol., DOI: 10.1038/nchembio.492).

The work is the first demonstration that steering clear of the active site is a viable design strategy for drugs that react to form a covalent bond to proteases, a broad class of proteins that includes many drug targets. This strategy has already proven useful for blocking other proteins such as kinases.

A team from the biotechnology company Avila Therapeutics developed the new protease blockers, which covalently bind to a cysteine in hepatitis C protease's substrate-binding site. In contrast, most other hepatitis C protease inhibitors in development reversibly bind to a catalytic amino acid common to proteases in human hosts as well as in viruses. Avila's published inhibitor structures are prototypes, but the company hopes to begin human clinical trials with optimized compounds in 2011. The team says its comprehensive structural analysis of hundreds of proteases suggests this strategy can be applied broadly

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However, it's not clear how applicable the team's strategy will be to all proteases, says Matthew S. Bogyo of Stanford University, who develops chemical tools to study the roles of proteases in disease. Nevertheless, "covalent inhibitors benefit from a long duration of action, and when used for clearing pathogens such as hepatitis C virus, they may make more sense than classical reversible inhibitors," Bogyo says. Covalent inhibitors can also make several aspects of drug development more straightforward because it's easier to monitor their target selectivity and distribution throughout the body compared with reversible inhibitors, he adds

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http://pubs.acs.org/cen/news/88/i49/8849news3.html