Biology subjects

Selvarajah, S.

Publications and source records attributed to Selvarajah, S..

3 recordsLinked to original sources

bioRxiv2025

Preclinical characterization of AT-03, a novel Serum Amyloid P fusion protein that demonstrates pan-amyloid binding and removal

The systemic amyloidoses are progressive disorders caused by extracellular deposition of insoluble amyloid fibrils leading to organ dysfunction that often proves fatal. New therapeutics aiming at removing deposited amyloid are urgently needed to improve patient outcomes. MethodsWe developped AT-03 (originally called SAP-scFc), a fusion protein consisting of serum amyloid P-component, which binds all types of amyloid, linked to a single chain human IgG1 Fc domain. AT-03 binding to diverse types of amyloid and phagocytic activity were assessed both in vitro and in vivo. Therapeutic efficacy was evaluated in an AA mouse model. ResultsAT-03 bound with high potency to AL and ATTR human amyloid extracts. In murine models, intravenously administered AT-03 bound to AA, AL and AApoA2 amyloid, including in the heart. Ex vivo AT-03 opsonization induced phagocytosis of human AL extract by activated human THP-1 macrophages and enhanced in vivo phagocytosis in mice. A single intravenous injection of SAP-scFc induced a significant reduction of splenic amyloid in a murine model of AA amyloidosis. ConclusionsAT-03 binds many amyloid types and can promote macrophage-mediated phagocytosis of the deposits. Thus, AT-03 is a promising novel therapeutic agent for the removal of systemic amyloid.

pathology↗

bioRxiv2023

Protein Assembly Modulation: A New Approach to ALS Therapeutics

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease with a complex, multifactorial pathophysiology, most commonly manifest as loss of motor neurons. We introduce a new mechanism of ALS pathogenesis via a novel drug-like small molecule series that targets protein disulfide isomerase (PDI) within a previously unappreciated transient and energy-dependent multi-protein complex. This novel drug was found to have activity in cellular models for both familial and sporadic ALS, as well as in transgenic worms, flies, and mice bearing a diversity of human genes with ALS-associated mutations. These compounds were initially identified as modulators of human immunodeficiency virus (HIV) capsid assembly in cell-free protein synthesis and assembly (CFPSA) systems, with demonstrated antiviral activity in cell culture. Their advancement as ALS-therapeutics, and the subsequent separation of activity against HIV and ALS in chemical subseries through structure-activity-relationship optimization, may provide insights into the molecular mechanisms governing pathophysiology of disordered homeostasis relevant to ALS.

neuroscience↗

bioRxiv2021

From COVID-19 to the Common Cold: Novel Host-Targeted, Pan-Respiratory Antiviral Small Molecule Therapeutics

We present a novel small molecule antiviral chemotype that was identified by an unconventional cell-free protein synthesis and assembly-based phenotypic screen for modulation of viral capsid assembly. Activity of PAV-431, a representative compound from the series, has been validated against infectious virus in multiple cell culture models for all six families of viruses causing most respiratory disease in humans. In animals this chemotype has been demonstrated efficacious for Porcine Epidemic Diarrhea Virus (a coronavirus) and Respiratory Syncytial Virus (a paramyxovirus). PAV-431 is shown to bind to the protein 14-3-3, a known allosteric modulator. However, it only appears to target the small subset of 14-3-3 which is present in a dynamic multi-protein complex whose components include proteins implicated in viral lifecycles and in innate immunity. The composition of this target multi-protein complex appears to be modified upon viral infection and largely restored by PAV-431 treatment. Our findings suggest a new paradigm for understanding, and drugging, the host-virus interface, which leads to a new clinical therapeutic strategy for treatment of respiratory viral disease.

biochemistry↗