Caprotec Bioanalytics GmbH
Capture Compound Mass Spectrometry – proteomics technology of choice for pharmaceutical and agrochemical R&D
Capture Compound Mass Spectrometry (CCMS) enables the direct identification of proteins that interact with small molecules such as drugs or agrochemicals. The core of the CCMS technology is proprietary chemistry that permits the construction around a small molecule of tri-functional Capture Compounds® (CCs), which enable the targeted isolation and identification of its target proteins directly from complex biological samples in solution.
In proteomics methodologies, CCMS has major advantages over ‘pull-down’ or activity-based probe approaches, as the CCs are constructed using a scaffold that contains separate reactivity and sorting functions which permit substantially unhindered access of the small molecule under investigation to its target proteins, and enable covalent capture of these proteins in a homogeneous phase. Attachment of the CC scaffold to different points in the molecule under investigation allows exposure of multiple pharmacophoric elements to gain a full picture of its interaction with the proteome (eg Fig 1).
The principle of on- and off-target ID
CCMS has been validated extensively by caprotec’s own studies, in collaboration with academia, and in its commercial interactions with industry partners, and has the following particular strengths:
• only one chemical modification of the investigational molecule is required
• the CC scaffold minimizes hindrance of small molecule–protein interaction
• no need for solid support in target recognition step
• unbiased profiling of interactions with endogenous proteins
• successful capture of cytoplasmic, intraorganellar and membrane-spanning targets
• applicability in intact and permeabilised cells as well as lysate
• successful identification from very small protein amounts
• very high cross-link yields
• determination of cross-linked peptides and sites of binding
• successful identification of low abundance and low affinity partners
• proven applicability to materials derived from plant and animals, from bacteria to man
CCMS applications in the preclinic: Target identification and validation, lead optimization and candidate selection
CCMS’ advantages confirm it as technology of choice for the deconvolution of unknown targets, mechanistic or toxicological, for small molecules. This forms the basis for ongoing collaborations between caprotec and the pharmaceutical, agrochemical and biotech industries, in which caprotec applies CCMS to discover for example the protein targets of small molecules identified by phenotypic screening, or to uncover secondary targets which may be relevant for pluripotent activities in certain molecules, or to identify the protein targets which may be responsible for unexpected or tissue- and species-specific toxicities.
The CC generated for target ID can be used also as tools to assist in target validation and drug optimization. For example, the covalent cross reactivity function intrinsic to the CC not only ensures very high recovery of captured proteins (up to 50%), permitting identification of low abundance partners as well as low affinity binders, but also allows the close localization of the binding site of the small molecule ligand to its target, generating invaluable starting information for any discovery campaign.
Moreover, CCs can be used as ligands to derive structure activity relationships at their target proteins, or even to screen compounds in place of a cell-based assay. Current studies are also evaluating potential uses in visualization and monitoring of target proteins in relevant tissues in health and disease.
CCMS applications in the clinic: Drug rescue
The cost of drug development is unacceptable for industry and society alike, and a significant contributor is failure in clinical trials.
CCMS can impact this also in positive ways:
• Identifying new targets for new indications
Application of CCMS to compounds which have failed in the clinic due to insufficient efficacy for their chosen indication will reveal novel targets and hence indications which may permit further development, leveraging the information already gathered in their initial development path, and reducing cost and risk.
• Personalizing medicines: Biomarker ID for stratification and monitoring
The ‘protein binding fingerprint’ delivered by CCMS can also identify compound-specific biomarkers for patient stratification or monitoring in clinical trials or use.
The potential for the use of CCMS to reduce risk and cost, and maximize value from expensive active ingredient developments is enormous. Accordingly, it is caprotec’s aim to establish CCMS as an enabling technology providing valuable information throughout the discovery, regulatory development and life cycle management of bioactive molecules.
For further information on collaborating and partnering, and to apply CCMS to solve your problem please contact us.
Prof. Dr. Hubert Köster
Founder & Managing Director/CEO