Investigating the mechanism of action of aggregation-inducing antimicrobial Pept-ins

Amyloid light-chain (AL) amyloidosis is the most common form of systemic amyloidosis in western countries.1 It is usually caused by the misfolding immunoglobulin light chains (LC) which are secreted by aberrant proliferating clonal plasma cells. The misfolding LC can aggregate and deposit in the form of amyloid fibrils in multiple tissues and organs, including heart, kidney, soft tissues, liver, peripheral, autonomic nervous system and/or gastrointestinal system.2-4 The tissue deposits can ultimately lead to organ dysfunction and failure. For many years, the treatment of AL amyloidosis has been focused on suppressing the plasma cells, in order to inhibit the abnormal production of LC and subsequently the formation of amyloid deposits.3,4 Despite the existing effective chemotherapy options, AL amyloidosis remains challenging, dangerous and often incurable. A major contributor to this challenge is that available chemotherapies leave the existing and circulating amyloid deposits unaddressed and untreated, which are cytotoxic and can cause further organ dysfunction and failure.5 A second contributor to the challenge of AL amyloidosis is delayed diagnosis which is due to the lack of a reliable diagnostic test and often results in poorer survival. 40% of the AL amyloidosis patients has been diagnosed over a year after the onset of the symptoms, leaving patients with irreversible and severe organ damage.3 Taken together, both the therapeutic interventions directly targeting the amyloid deposits and the diagnosis of AL amyloidosis needs to be improved, which requires a more detailed understanding of the aggregation mechanism of AL amyloidosis. Numerous studies have been carried out to research the factors which render the LC amyloidogenic. From the genetic aspect, some overrepresented germline gene products and different mutations in AL amyloidosis have been reported to be aggregation prone.2,4 In addition to the genetic aspect, it is hypothesised that certain unstable segments which contain aggregation prone regions are critical for the formation of amyloid deposits.4 Therefore, several methods, which can accurately predict the critical amyloidogenic segments of primary protein sequence, have been established in order to predict the protein aggregation propensity.7-10 However, even though most proteins are well folded under native conditions, a very small number of critical aggregation prone regions that remain (partially) exposed to the solvent in the folded protein are key to understand the aggregation propensity of such folded proteins.11 Thus, this project aims to study the aggregation mechanism of LsC in vitro, in silico, and in vivo, which may provide significant benefit the development of a reliable diagnostic test and the improvement of amyloid-directed antibody treatment of AL amyloidosis. Reference Lin, H. M. et al. Disease burden of systemic light-chain amyloidosis: a systematic literature review. Curr. Med. Res. Opin. 33, 1017-1031 (2017). 2. Ramirez-Alvarado, M. Amyloid formation in light chain amyloidosis. Curr. Top. Med. Chem. 12, 2523-33 (2012). 3. Palladini, G. & Merlini, G. Perspectives What is new in diagnosis and management of light chain amyloidosis? Blood 128, 159-169 (2016). 4. Merlini, G. et al.. Systemic light chain amyloidosis: An update for treating physicians. Blood 121, 5124-5130 (2013). 5. Richards, D. B. et al. Therapeutic Clearance of Amyloid by Antibodies to Serum Amyloid P Component. N. Engl. J. Med. 373, 1106-1114 (2015). 6. Gertz, M. A. et al. First-in-human phase I/II study of NEOD001 in patients with light chain amyloidosis and persistent organ dysfunction. J. Clin. Oncol. 34, 1097-1103 (2016). 7. van der Kant, R. et al. Prediction and Reduction of the Aggregation of Monoclonal Antibodies. J. Mol. Biol. 429, 1244-1261 (2017). 8. Xu, J. et al. Gain of function of mutant p53 by coaggregation with multiple tumor suppressors. Nat Chem Biol 7, 285-295 (2011). 9. De Baets, G. et al.. Increased Aggregation Is More Frequently Associated to Human Disease-Associated Mutations Than to Neutral Polymorphisms. PLoS Comput. Biol. 11, 1-14 (2015). 10. Fernandez-Escamilla, et al. Prediction of sequence-dependent and mutational effects on the aggregation of peptides and proteins. Nat. Biotechnol. 22, 1302-1306 (2004). 11. Ganesan, A. et al. Structural hot spots for the solubility of globular proteins. Nat. Commun. 7, 10816 (2016).

Publication year:2021