Biology subjects

Ford, D. J.

Publications and source records attributed to Ford, D. J..

3 recordsLinked to original sources

bioRxiv2026

Chemical Synthesis of Thrombostasin: An Anticoagulant Protein Produced by the Horn Fly Haematobia irritans

Thrombostasin is a cysteine-free anticoagulant protein produced by the horn fly Haematobia irritans, featuring an unusual stretch of seven consecutive aspartate residues within the polypeptide sequence. Here, we report the first chemical synthesis of native thrombostasin and a hepta-glutamate analogue, together with assessment of their thrombin inhibitory and anticoagulant activity.

molecular biology↗

bioRxiv2023

Development of supramolecular anticoagulants with on-demand reversibility

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 (hours to days for small molecules, weeks to months for biologics). In some cases, it is important to achieve a fast reversal of the drugs action to overcome dangerous side effects or in response to unforeseen events. A case in point is for anticoagulant drugs. Here we report a general strategy to achieve on-demand reversibility by leveraging supramolecular assembly of drug fragments and showcase the approach with thrombin-inhibiting anticoagulants. In our supramolecular drug design, the action of the drug is reinforced by a dynamic hybridisation of peptide nucleic acids (PNAs) between drug fragments. We show that this design enables the generation of very potent bivalent direct thrombin inhibitors (Ki 74 pM) and this inhibition can be reversed through the use of a PNA antidote. We demonstrate that these supramolecular inhibitors exhibit potent anticoagulant activity in vitro and in vivo and that this activity can also be reversed on demand.

biochemistry↗

bioRxiv2021

The MLR COMPASS-like complex is required to regulate triglyceride depletion and stress response in the Drosophila fat body

MLR COMPASS-like complexes are highly conserved histone modifiers and enhancer regulators recruited by multiple transcription factors during differentiation and development, including lineage-determining factors, nuclear receptors, and developmental signaling pathway effectors. While the essential functions of MLR complexes during differentiation-associated transcriptional reprogramming has been well-explored, roles that these complexes play during reprogramming events in terminally differentiated cells remain understudied. We determined that the Drosophila MLR complex is required in fat body adipocytes for proper regulation of the triglyceride depletion rate during non-feeding periods, including metamorphosis and adult starvation. Transcriptome analysis revealed that the complex plays a critical role in controlling stress-related reprogramming in these cells, suggesting that the metabolic phenotypes are indirect effects of dysregulated stress transcription. Furthermore, our evidence suggests that the complex interacts with Foxo and Relish (Nf-{kappa}b) pathways and is required for proper expression of their targets. This investigation further elucidates the necessary functions of MLR complexes in regulating transcriptional reprogramming in terminally differentiated cells as well as suggests novel binding partners. Apparent roles for these complexes in the proper regulation of stress-induced transcription implies new mechanisms involved in cancer and other human diseases associated with MLR subunit mutation.

genetics↗