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- Title
Assembly of Biologically Functional Structures by Nucleic Acid Templating: Implementation of a Strategy to Overcome Inhibition by Template Excess.
- Authors
Lawler, Matthew M.; Kurnick, James T.; Fagundes St. Pierre, Leah; Newton, Estelle E.; Rose, Lenora B.; Dunn, Ian S.
- Abstract
Delivery of therapeutic molecules to pathogenic cells is often hampered by unintended toxicity to normal cells. In principle, this problem can be circumvented if the therapeutic effector molecule is split into two inactive components, and only assembled on or within the target cell itself. Such an in situ process can be realized by exploiting target-specific molecules as templates to direct proximity-enhanced assembly. Modified nucleic acids carrying inert precursor fragments can be designed to co-hybridize on a target-specific template nucleic acid, such that the enforced proximity accelerates assembly of a functional molecule for antibody recognition. We demonstrate the in vitro feasibility of this adaptation of nucleic acid-templated synthesis (NATS) using oligonucleotides bearing modified peptides ("haplomers"), for templated assembly of a mimotope recognized by the therapeutic antibody trastuzumab. Enforced proximity promotes mimotope assembly via traceless native chemical ligation. Nevertheless, titration of participating haplomers through template excess is a potential limitation of trimolecular NATS. In order to overcome this problem, we devised a strategy where haplomer hybridization can only occur in the presence of target, without being subject to titration effects. This generalizable NATS modification may find future applications in enabling directed targeting of pathological cells.
- Subjects
IMMUNOGLOBULINS; OLIGONUCLEOTIDES; NUCLEIC acids; TRASTUZUMAB; MOLECULES; VOLUMETRIC analysis; PEPTIDES
- Publication
Molecules, 2022, Vol 27, Issue 20, p6831
- ISSN
1420-3049
- Publication type
Article
- DOI
10.3390/molecules27206831