Bicyclic peptides with optimized ring size inhibit human plasma kallikrein and its orthologs while sparing paralogous pr

Apr 13, 2012
Bicyclic peptides with optimized ring size inhibit human plasma kallikrein and its orthologs while sparing paralogous proteases

(Phys.org) -- New drug candidates require testing in animal models prior to approval for clinical use. A recently developed antagonist based on a bicyclic peptide inhibited the human serine protease plasma kallikrein potently and selectively. However, the inhibitor was ‘too’ selective, not inhibiting murine plasma kallikrein which prevented its testing in animal models. Researchers led by Christian Heinis have developed bicyclic peptides that inhibit both human and murine plasma kallikrein, but not any paralogous proteases; their work is reported in ChemMedChem.

"We compared structural models of target (and related non-target) proteases to identify conserved regions in the vicinity of the active site, and modulated the loop size of our libraries of peptide macrocycles accordingly," says Heinis on behalf of his team at the Swiss Federal Institute of Technology in Lausanne and colleagues John Tite (Bicyclic Therapeutics) and Greg Winter (Laboratory of Molecular Biology; both Cambridge, UK). "From these libraries, we were able to isolate potent bicyclic peptide inhibitors of human, rat and monkey plasma kallikrein that do not inhibit related human serum proteases."

Based on structural considerations, the authors hypothesize that the length of the peptide loops may influence specificity. By modulating the loop size of the peptide macrocycles, they succeeded in selecting potent human plasma kallikrein inhibitors with the desired specificity profile. Heinis states further that "...the bicyclic combine key qualities of antibody therapeutics (high affinity and specificity) and advantages of small-molecule drugs and may offer an attractive format for the development of therapeutics." The authors conclude that this strategy will likely facilitate the use of peptide macrocycles in animal models, while avoiding unwanted off-target activities in the clinic.

Explore further: Structure of sodium channels different than previously believed

More information: Christian Heinis, Bicyclic Peptides with Optimized Ring Size Inhibit Human Plasma Kallikrein and its Orthologues While Sparing Paralogous Proteases, ChemMedChem, dx.doi.org/10.1002/cmdc.201200071

add to favorites email to friend print save as pdf

Related Stories

Active compounds against Alzheimer's disease

Jan 12, 2012

More than half of all cases of dementia in the elderly can be attributed to Alzheimer's disease. Despite vast research efforts, an effective therapy has not been developed, and treatment consists of dealing with the symptoms. ...

Understanding the APJ Receptor Binding Site

Jun 01, 2010

(PhysOrg.com) -- Apelin is a recently discovered peptide that binds to the apelin (or APJ) G-protein-coupled receptor. Apelin-13 (NH2-QRPRLSHKGPMPF-COOH), one of several cleavage products of the proprotein ...

Recommended for you

Breakthrough points to new drugs from nature

Apr 16, 2014

Researchers at Griffith University's Eskitis Institute have developed a new technique for discovering natural compounds which could form the basis of novel therapeutic drugs.

World's first successful visualisation of key coenzyme

Apr 16, 2014

Japanese researchers have successfully developed the world's first imaging method for visualising the behaviour of nicotine-adenine dinucleotide derivative (NAD(P)H), a key coenzyme, inside cells. This feat ...

User comments : 0

More news stories

Impact glass stores biodata for millions of years

(Phys.org) —Bits of plant life encapsulated in molten glass by asteroid and comet impacts millions of years ago give geologists information about climate and life forms on the ancient Earth. Scientists ...

Airbnb rental site raises $450 mn

Online lodging listings website Airbnb inked a $450 million funding deal with investors led by TPG, a source close to the matter said Friday.

Health care site flagged in Heartbleed review

People with accounts on the enrollment website for President Barack Obama's signature health care law are being told to change their passwords following an administration-wide review of the government's vulnerability to the ...