Development of Supramolecular Anticoagulants with On-demand Reversibility

Overview

Journal Nat Biotechnol

Specialty Biotechnology

Date 2024 Apr 30

PMID 38689027

Authors

Millicent Dockerill

Daniel J Ford

Simona Angerani

Imala Alwis

Luke J Dowman

Jorge Ripoll-Rozada

Rhyll E Smythe

Joanna S T Liu

Pedro Jose Barbosa Pereira

Shaun P Jackson

Richard J Payne

Nicolas Winssinger

Affiliations

Soon will be listed here.

Abstract

Drugs are administered at a dosing schedule set by their therapeutic index, and termination of action is achieved by clearance and metabolism of the drug. In some cases, such as anticoagulant drugs or immunotherapeutics, it is important to be able to quickly reverse the drug's action. Here, we report a general strategy to achieve on-demand reversibility by designing a supramolecular drug (a noncovalent assembly of two cooperatively interacting drug fragments held together by transient hybridization of peptide nucleic acid (PNA)) that can be reversed with a PNA antidote that outcompetes the hybridization between the fragments. We demonstrate the approach with thrombin-inhibiting anticoagulants, creating very potent and reversible bivalent direct thrombin inhibitors (K = 74 pM). The supramolecular inhibitor effectively inhibited thrombus formation in mice in a needle injury thrombosis model, and this activity could be reversed by administration of the PNA antidote. This design is applicable to therapeutic targets where two binding sites can be identified.

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