MATCH™ (Macrocyclic Template Chemistry) is Tranzyme’s proprietary drug discovery and medicinal chemistry technology. Tranzyme has successfully used this chemistry technology to produce several developmental and clinical stage drug candidates. With MATCH™, for the first time, the construction of synthetic libraries of drug-like, orally administered macrocyclic compounds can be conducted in a highly predictable and efficient manner. MATCH™ is a chemistry breakthrough with broad application to accelerate drug discovery.
Tranzyme’s macrocycles are a distinct class of small molecules with defined and predictable shapes. Although many macrocyclic compounds from natural sources or with complex chemistries have been successfully developed as marketed drugs, Tranzyme’s compounds represent the first completely synthetic and systematically synthesized collection of macrocycles. MATCH™ allows, for the first time, the efficient and predictable construction of synthetic libraries of these molecules. In the past, the potential of macrocycles as attractive drugs has been largely underutilized. Tranzyme now makes these unique compounds available for pharmaceutical drug discovery.
MATCH™ compounds mimic the favorable binding characteristics of proteins and peptides such as tight receptor binding for high potency and selectivity, while eliminating the drawbacks associated with biomolecules such as poor metabolic stability, low oral bioavailability, lack of membrane permeability, high manufacturing costs, and antigenicity.
In order to attain high affinity and to bind selectively to a targeted receptor, a successful mimetic must reproduce both the functionality and the orientation of the receptor-bound peptide ligand. As shown in the figure below, Tranzyme macrocycles incorporate three recognition moieties locked in a defined, cyclic, three-dimensional structure by a proprietary non-peptide chemical fragment called a tether, having a molecular weight of 100-200. The recognition moieties originate from either natural or non-natural amino acids. MATCH™ enables Tranzyme to vary these tethers in order to control and modulate spatial orientation. While the recognition moieties provide the elements that interact with targeted receptor, the tethers define and control their unique conformation, ensuring tighter binding and improved potency. MATCH™ also enables the incorporation of recognition elements other than amino acids to explore the effects of other functionalized building blocks.
A demonstration of the effects of the proprietary non-peptide tether (T1, T2, T3) on molecular shape and display of recognition elements (X, Y, Z). Tranzyme has synthesized more than 100 tethers and used them for optimization. The defined topology often leads to significant drug activity of initial hits.