The dimethoxytrityl resin product anchored sequential synthesis method (DMT PASS): a conceptually novel approach to oligonucleotide synthesis

Presented is a conceptually novel approach to oligonucleotide synthesis ref erred to herein as dimethoxytrityl resin product anchored sequential synthe sis (DMT PASS). The DMT PASS process is characterized by the reaction of a 3'-protected nucleoside or oligonucleotide with an excess of a nucleotide 3 '-phosphoramite or H-phosphonate which is bound to a dimethoxytrityl functi onalized polystyrene resin, As a result, successfully coupled oligonucleoti de product is then attached to the solid support, allowing for removal and potential recovery of starting materials. The protected oligonucleotide pro duct is then released and subjected to an aqueous/organic extractive purifi cation, which serves to remove monomeric impurities. The PASS process is an ticipated to provide for the cost-effective manufacture of oligonucleotides on a scale which would allow for clinical development and pharmaceutical p roduct commercialization. Herein we describe some aspects of our process de velopment progress and discuss preliminary applications of the process to t he synthesis of short oligodeoxyribonucleotide sequences, as well as a numb er of challenges confronting the PASS development effort.