Development of novel therapeutics for cardiovascular disorders via a multidisciplinary combination of phage display and organic chemistry (LFA.5952)

Project nummer: lfa5952

Omschrijving van het onderzoek

Atherosclerosis related cardiovascular diseases (CVD) are the foremost cause of death in Western society. While successful, current drug therapy still appears to be inadequate in completely curing or preventing disease in the majority of patients. For this new therapies that specifically target the disease process and diagnostic tools to stratify those patients at immediate risk for acute cardiovascular syndromes are awaited. New factors have been identified, including receptors, effector molecules and enzymes, that appear ideal candidate targets for drug intervention. We here propose a new approach for the rapid generation of novel leads for therapeutic intervention in atherosclerosis through a unique combination of molecular biological and organic chemical combinatorial drug design. In the first stage peptide leads will be identified for new cardiovascular targets by phage display and the most effective peptides will be used as starting point for subsequent organic chemical optimization, combining the strength of completely unbiased selection from large phage displayed libraries (>200x106) with directed organic chemical optimisation of the initial peptide leads. The high flexibility and rapidity renders this strategy eminently fit not only for new drug design in CVD therapy but also in anti-inflammatory and cancer therapy.
In this project, we will develop and exploit a novel strategy for the generation of compounds interfering with inflammatory processes within lesions that are at risk for cardiovascular disease. The strategy involves the powerful, hitherto undervalued combination of phage displayed peptide repertoire cloning for rapid identification of new leads with (combinatorial) organic chemistry for subsequent lead optimisation. As shown earlier for the design of potent P-selectin antagonists (Eur Patent 11303314.8), the rapidity and partly unbiased character of this approach is a clear advantage in new drug design. Due to their expected novelty and their high capacity to image and/or intervene in key processes critical to acute cardiovascular syndromes, the leads will represent an important addition to the available diagnostic and drug armament.

Gebruikers

Er zijn drie bedrijven en één andere universiteit bij dit project betrokken.

Projectleider

Dr.ir. E.A.L. Biessen

Universiteit Leiden
Wiskunde en Natuurwetenschappen
Leiden/Amsterdam Centre Drugs Research

Postbus 9503
2300 RA Leiden

Status van het project

Gestart	: 01-01-2003
Einddatum	: 01-09-2007

Trefwoorden

Atherosclerose, Cardio-vasculair, Drug development, Farmacochemie, Geneesmiddelen, Organische chemie, Peptidomimetica, Phage display, Pharma.

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