DNA-encoded libraries having encoding oligonucleotide linkages not readable by polymerases
The present invention relates to complexes of oligonucleotide-encoded libraries and methods of tagging and using such libraries. In particular, the oligonucleotides and methods can include complexes having at least one linkage for which a polymerase has reduced ability to read or translocate through.
1. A complex comprising:
(i) a chemical entity comprising one or more scaffolds or one or more building blocks;
(ii) a headpiece having a first functional group operatively associated with said chemical entity and a second functional group operatively associated with an a first oligonucleotide tag via a first linkage;
(iii)-n number of additional oligonucleotide tags having n additional linkages, wherein n is 1, 2, 3, 4, 5, 6, 7, 8, or 9, and wherein each of said additional linkages is between two adjacent tags and each tag encodes the identity of at least one of said one or more scaffolds or building blocks; and
wherein at least one of said n additional linkages is a cross-linking oligonucleotide that spans the junction between two adjacent tags, and that operatively associates with said two adjacent tags via one or more reversible co-reactive groups, wherein at least one of said one or more reversible co-reactive groups is a cyanovinylcarbazole.
2. The complex of claim 1 , wherein at least two of said first linkage and n additional linkages comprise:
a cross-linking oligonucleotide that spans the junction between said second functional group and said first tag or between two adjacent tags and that operatively associates with said second functional group and said first tag or with said two adjacent tags via one or more reversible co-reactive groups, wherein at least one of said one or more reversible co-reactive groups is a cyanovinylcarbazole.
3. The complex of claim 1 or 2 , wherein one or more tags comprise a 5′-connector at the 5′-terminus of said one or more tags and a 3′-connector at the 3′-terminus of said one or more tags.
4. The complex of claim 1 , wherein less than about 50% of said first linkage and n additional linkages comprise an enzymatic linkage.
5. The complex of claim 1 , wherein said chemical entity is operatively associated to said headpiece via a bifunctional spacer.
6. The complex of claim 1 , wherein said chemical entity is covalently attached to said headpiece.
7. The complex of claim 1 , wherein said headpiece comprises an oligonucleotide selected from the group consisting of a double-stranded oligonucleotide, a single-stranded oligonucleotide, or a hairpin oligonucleotide.
8. The complex of claim 7 , wherein said headpiece comprises a primer-binding region.
9. The complex of claim 1 , further comprising one or more first library-identifying tag(s), use tag(s), and/or origin tag(s).
10. The complex of claim 1 , wherein said complex comprises RNA, DNA, modified DNA, and/or modified RNA.
11. The complex of claim 1 , further comprising a tailpiece.
12. A library comprising one or more complexes of claim 1 .