Probing the antiamyloidogenic activity of D,L-α-cyclic peptides on the aggregation mechanism of light chain amyloidosis

Systemic light chain amyloidosis (AL) stems from a clonal plasma cell disorder in the bone marrow leading to abnormal proliferation and aggregation of immunoglobulin light chain (LC) amyloid deposits.¹ Most AL cases result in cardiomyopathy and heart failure with poor survival ratio and they are often accompanied by multi-organ dysfunction primarily in kidney, liver and nerves.² Due to their structural resemblance to amyloids, cyclic D,L-α peptides carry great potential in modulating aggregation kinetics by inhibiting the aggregation and disintegrating the fibrils into non-amyloidogenic components.^3,4 Accordingly, our aim is to substantiate the efficacy of these cyclic peptides in inhibiting AL aggregation and toxicity and understand the underlying molecular mechanisms by biochemical and biophysical techniques and cytotoxicity studies.

Our model system is comprised of two recombinant LCs, the aggregation-prone SMA variant and the benign LEN, whose sequence differs at 8 amino acid positions. Both proteins were expressed and purified using standard protocols and then subjected to Thioflavin T (ThT) assays aiming at study of their fibrillation kinetics. Nuclear magnetic resonance (NMR) detected the binding of the cyclic peptide to LEN and SMA providing structural clues to the dynamic interaction of different residues leading to elucidation of the binding region and site specific molecular interactions between LCs and the cyclic peptide. Overall, the present study aims to elucidate the mechanistic underpinnings of AL cardiac amyloidosis with therapeutic agents that can target AL deposits and prevents the LC mediated assembly and cytotoxicity.