Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2000-09-07
2003-02-18
Fredman, Jeffrey (Department: 1637)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S026600, C536S018700, C530S333000, C530S338000, C435S006120
Reexamination Certificate
active
06521744
ABSTRACT:
Subject of the present invention is a method for constructing a 2- or 3-dimensional defined polymeric geometric structure from oligomeric elements, such geometric structures as well as the use of nucleic acid analogues in assembling of supramolecular structures of defined form.
Living organisms are build from biomolecules particularly by defined self association of such biomolecules (lipids, protein complexes and DNA double helix). Such supramolecular structures occurring in living organisms are relatively unstable outside of these organisms, because the biomolecules have only limited affinity and are biologically degradable.
Lehn (Science 260, 1762-1763, 1993) describes the use of artificial self assembled complexes from low molecular weight organic molecules and metal ions.
It is further known that holes can be created in Longmuir-Blodget-layers during cluster formation. Such artificial systems are based on the association of uniform molecules having no or small differences.
In nature complex structures are made up from macro molecules of different tertiary structures, based upon uniform basic structures like amino acids and nucleotides. Nucleic acids of complementary sequence form helical chains which can form later in-vivo special structures and networks.
In Angew. Chem. Int. Ed. Engl. 1997, 36, 7, 735-739 a supramolecular structure based on macrocycles is disclosed. In J. Am. Chem. Soc. 1997, 119, 852-853, control of stereochemistry in supramolecular architecture is described.
In J. Vac. Sci. Technol. A 12(4), 1895-1903, there is described the self-assembly of DNA molecules to form a 2-dimensional latice. Such latices are formed using DNA molecules the nucleotide sequence of which is chosen such that four or more of such DNA molecules have a preferred assembly to form a junction. There is explicit explanation in this document how the sequences of the DNA molecules involved has to be chosen. Further there is at least theoretical disclosure how a 3-dimensional object, like a cube, can be created from 6 cyclic DNA molecules. Again, the sequences of the DNA molecules are chosen such that the structure is stabilized and defined by the formation of double stranded DNA along the edges of the cube.
In DE-A-3924454 and U.S. Pat. No. 5,561,071 there is described the use of self-assembled double stranded DNAs for forming conducting elements, for example elements used in electronic chips. The disclosure of this reference is incorporated by reference into the present specification.
The supramolecular structures prepared by self-assembly of DNA have now been found to be so unstable under in vitro conditions that, for example electronic chips prepared by them are not reliable.
In WO 92/20702 there are disclosed purely synthetic oligomeric molecules which are capable of binding to complementary nucleic acids with very high affinity. This can be used for either therapy within the human body or in the diagnosis of nucleic acids in vivo or in vitro. Peptide nucleic acids (PNAs) as described in this reference are characterized by having a non-naturally occurring backbone having attached nucleobases at defined positions, such that these nucleobases can hydrogen bond to the complementary bases on a DNA strand, thus forming a double or triple stranded complex.
It was therefore an object of the present invention to provide high molecular weight supramolecular structures in a more reliable way.
It was an alternative or additional object of the present invention to provide more stable high molecular weight supramolecular structures in a predictable way.
In a further object of the present invention to provide new materials based on supramolecular structures in an intended way, which can be used in computer chips, in roboting, such as robot arms in nanometer scale, in new materials/polymers with conductivity and/or insulator properties.
Subject of the present invention is therefore a method for constructing a 2- or 3-dimensional defined polymeric geometric structures comprising the steps of combining a first oligomeric element having bound recognition elements with a second oligomeric element having bound recognition elements capable of recognizing the recognition elements of said first oligomeric element at binding conditions, wherein said recognition elements are heterocyclic moieties recognizing other recognition elements via hydrogen bonding and wherein said recognition elements of said first and second oligomeric element are bound to spaced defined locations of a peptide bond containing backbone. A further subject of the present invention are such polymeric geometric structures.
FIG. 1
shows the structure of a self-assembled 2-dimensional geometric structure prepared by self-assembly of three different peptide nucleic acids.
A defined geometric structure according to the present invention is a structure having a defined expansion and which can be drawn schematically. Examples of such defined geometric structures are latices, junctions, cubes and branched molecules as described in the above mentioned prior art. Therefore, the invention can be used in nano-engineering to create intended structures. While the prior art describes DNA for making up the structure, the present invention is directed to the use of oligomeric elements comprising a peptide like bond containing backbone. The geometric structures preferably contain at least one branching point. A branching point is defined to be the location where three or more arms meet. At least one of these arms comprises a segment wherein one strand of this arm is bound to a strand of a further oligomeric element. The oligo- or polymeric geometric structure according to the present invention comprise at least two oligomeric elements. However, it is preferred that such a structure contains 6 or more, preferably between 8 and 1 Million oligomeric elements. In this definition oligomeric structures will contain from 2 to 20 and polymeric structures more than 21 oligomeric elements. These oligomeric elements can be of the same kind, for example only differing in the sequence of the recognition elements, preferably, however, the oligomeric elements are of a different kind, for example differing in sequence and in molecular structure, for example some of them being modified further or being based on different backbones or moieties attached.
An oligomeric element according to the invention is defined to contain affinity moieties, such as alkyl, aryl, aromatic or/and heterocyclic moieties recognizing other heterocyclic molecules via van-der-Waals interaction, &pgr;-stacking, water exclusion or hydrogen bonding. Said affinity moieties are bound to spaced defined locations of a polyamide backbone. The backbone is generally a non-naturally occurrin backbone. The backbone preferably contains repetitive monomeric subunits, such subunits being covalently bound together, preferably using amide bond formation. While it is much preferred to use only one kind of monomeric subunit in the backbone, it is possible to use different subunits and/or different bonds within the backbone either mixed individually or as stretches containing several identical subunits, as described in WO 95/14706, EP 700928, EP 646595 and EP 672677.
Oligomeric elements having both a non-natural backbone part as well as an excessable oligonucleotide and can be used to postmodify the geometric structure after assembly. Thus, it is possible to attach further mononucleotide units to the end of the oligomeric unit, for example as described in EP 720615.
Preferred oligomeric elements, such as peptide nucleic acids (PNAs), are described in WO 92/20702. Such compounds comprise a containing polyamide backbone bearing a plurality of heterocyclic moieties that are individually bound to amine atoms located within said backbone.
Preferred peptide nucleic acids are shown in formula I:
wherein
n is an integer of from at least 3,
x is an integer of from 2 to n−1,
each of L
1
-L
n
is a ligand independently selected from the group consisting of hydrogen, hydroxy, (C
1
-C
4
)alkanoyl, naturally occurring nuc
Batz Hans-Georg
Hansen Henrik Frydenlund
Koch Troels
Arent Fox Kintner Plotkin & Kahn
Fredman Jeffrey
Maupin Christine
PNA Diagnostics A/S
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