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Monomer and Ligand
The monomer and the ligand that are not commercially available, made where the sequence is made.
The building block as a programme risk
A discovery design that calls for a monomer nobody sells is a design that does not get tested. A modified amidite with one supplier and a long lead time has the same effect more slowly.
Making the monomer where the oligonucleotide is made removes the dependency, the shipping and the second set of specifications, and means the impurity profile of the building block and the impurity profile of the sequence are understood by the same people.
Amidite synthesis
More than 1,000 customized amidite molecules, including the most challenging structures, with more than 500 amidite catalog products readily available.
Modifications run across the whole molecule:
- 2′, 3′ and 4′ modification with GalNAc moiety, lipid, amine or alkyne
- Sugar skeleton modification: bicyclic sugar, aza and thio sugar, acyclic sugar
- Base modification: 7-deaza A and G, pseudouridine, N-Me pseudouridine
- Therapeutic RNA modifications: 2′-OMe, 2′-F, 2′-O-MOE
- Phosphorus backbone modification: PACE, thiophosphoramidite, MeP, EtP
- Base protecting alternatives: Bz, Ac, iBu, pac and iPr-pac, O-NPE
- Functional and conjugate modifiers: phosphate reagents, amino and thiol linkers, spacers, cholesterol, dye
Sample molecules include RNAi amidite (2′-F, OMe, MOE, OTBS), LNA amidite, TNA amidite, Vpm-POM, DNA C(Bz) amidite, PACE amidite, thio-amidite and PMO monomer.
GalNAc
N-acetylgalactosamine is an amino sugar derivative of galactose, and conjugation with GalNAc is an efficient way to raise siRNA accumulation in the target organ and help cellular uptake.
We have made more than 100 types of GalNAc molecule: mono-, tri- and tetra-GalNAc, GalNAc amidite, GalNAc PFP ester, GalNAc azide and GalNAc-PEG conjugates among them. With more than 100 GalNAc building blocks and CPG and polystyrene conjugate resins behind it, the platform supports GalNAc-oligonucleotide programs from the first screening set onward.
Where GalNAc synthesis goes wrong, and what we changed
GalNAc is synthetically awkward because most of the intermediates are oily or foamy solids. The synthesis then needs many column and prep-HPLC purification steps, which makes scale-up difficult and yields low. The analytical work is equally awkward: low UV response, a complex impurity profile and poor stability.
We developed convergent routes through telescoping processes with no column purification steps, so that the isolated intermediates are stable solids rather than oils. Precipitation and spray drying reduce the need for columns and prep-HPLC. Our analytical teams identified a large number of GalNAc-related impurities to support method development and release testing.
The same monomer at GMP scale
A monomer chosen in discovery becomes a regulatory starting material later. More than 40 catalog amidites are available at commercial scale with Drug Master Files already filed, which is what allows the building block to be cited by reference number rather than documented in the sponsor’s own submission.
