Abstract
Syntheses of novel semi-orthogonally protected CycloTriVeratrilene (CTV) analogues with enhanced water solubility, that is 3 and 4, derived from the previously described CTV scaffold derivative 2 are described here. These scaffolds 2-4 enabled a sequential introduction of three different complementarity determining region (CDR) mimics via Cu(i)-catalysed azide-alkyne cycloaddition towards medium-sized protein mimics denoted as "synthetic antibodies". The highly optimised sequential introduction enabled selective attachment of three different CDR mimics in a one-pot fashion. This approach of obtaining synthetic antibodies, demonstrated by the synthesis of paratope mimics of monoclonal antibody infliximab (Remicade®), provided a facile access to a range of (highly) pre-organised molecules bearing three different (cyclic) peptide segments and may find a wide range of applications in the field of protein-protein interaction disruptors as well as in the development of synthetic vaccines or lectin mimics. The prepared synthetic antibodies were tested for their affinity towards tumour necrosis factor alpha using surface plasmon resonance and synthetic antibodies with micromolar affinities were uncovered.
Highlights
For several years we have been interested in the molecular construction and further development of protein mimics toward medium-sized molecule alternatives of biologics such as antibodies and vaccines.[1,2,3,4] In this area, we are facing several important challenges, which may determine a successful outcome of this quest
One challenge of our continuous attention is the development of pre-organized molecular scaffolds as the core molecular unit for attaching complementarity determining region (CDR)-loops mimics
Mono ethylene glycol 6a and diethylene glycol 6b were treated with sodium hydride and potassium tert-butoxide, respectively, followed by a treatment with propargyl bromide to yield the corresponding propargyl ether derivatives 7a and 7b
Summary
For several years we have been interested in the molecular construction and further development of protein mimics toward medium-sized molecule alternatives of biologics such as antibodies and vaccines.[1,2,3,4] In this area, we are facing several important challenges, which may determine a successful outcome of this quest. Paper added to the reaction mixture to selectively remove the TES protecting group[11] and without intermediate purification the CDR-mimicking peptide loop 30 was introduced via CuAAC leading to the two CDR loop mimic containing CTV derivatives.
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