Missing residues were modeled by template-based homology modeling using the server [34]

Missing residues were modeled by template-based homology modeling using the server [34]. by a few mutations to bind fresh amyloid sequences, providing an efficient way to reposition a restorative antibody to target different amyloid diseases. Keywords:-amyloid, amyloid light chain, amyloidosis, mAb, antibody design == 1. Intro == Protein aggregation diseases (commonly known as amyloidoses) are caused by pathologic processes with protein fibril deposition in such organs as the brain, heart, liver, pancreas, kidneys, and lungs, resulting in structural damage and dysfunction [1]. Amyloidosis can be classified based on the types of precursor proteins, as well as their localized or systemic deposition [1,2]. Systemic amyloidosis can be associated with protein deposits in any part of the body, such as systemic light chain amyloidosis due to the build up of immunoglobulin light chain amyloid fibrils. Most diseases, including Alzheimers disease (AD), Parkinsons disease (PD), and prion (mad cow), impact the nervous system, leading to the loss of neuronal structure and Col4a5 function [1,2,3]. Alzheimers disease is one of the most devastating neurodegenerative diseases without effective therapies [4]. Several strategies have been developed to reduce A production, inhibit aggregation, or directly enhance clearance. Using antibodies and their fragments has been a major approach [5,6,7]. Crenezumab is definitely a fully humanized immunoglobulin isotype G4 (IgG4) anti-A monoclonal antibody, which is currently in phase III study [8]. It is designed to bind multiple forms of A (monomers, oligomers, fibrils, and plaques), especially those with high affinity to oligomeric forms. Crenezumab binds both A1-40 and A1-42, and its ability to block A aggregation, promote A disaggregation of oligomers, and protect neurons from oligomer-induced cytotoxicity has been shown in vitro [9]. Regrettably, crenezumab failed in medical phase III in June 2022. We hope that crenezumabs medical trial could be continued with improvement, similarly to Aducanumab. Amyloid light chain (AL) amyloidosis, as an independent disease uncorrelated with AD, is Phloroglucinol the most common main systemic amyloidosis [10,11,12,13] and is difficult to treatment [14]. It is caused by insoluble protein dietary fiber deposition of light chain amyloid precursor in different tissues induced Phloroglucinol from the clonal proliferation of plasma cells [15]. In contrast to the highly focused restorative study on Alzheimers disease, there are very few antibodies that could bind Phloroglucinol or inhibit AL amyloid aggregation to opposite or halt the course of the disease [14,16,17,18,19]. The best monoclonal antibody, CAEL-101 (11-1F4), offers just finished its phase 1a/b study in AL individuals [20]. The structural details of the AL amyloids have been revealed by biological experiments [18,21], computational simulation [22], solid-state NMR [23], and recent cryo-EM experiments [24,25]. Loop flip at Pro8 of LC was previously proposed to lead to a -sheet conformation by inserting residues 17 into the -strands between residues 915 and 1626 [18]. Partial unfolded dimers were suggested to be within the pathways of AL amyloid formations [21]. Based on the loop flip of the N-terminal region, a modeled structure of AL fibril with misfolded dimer was analyzed [22]. A solid-state NMR experiment indicated that AL amyloid may have a nonnative structure [23]. However, five recent cryo-EM experiments of the light chain AL fibrils from cardiac amyloidosis individuals have shown two totally different AL fibril folds [24,25,26,27]. The entire N-terminal is revealed on four fibril constructions [24,26,27], while in Swuec et al.s structure [25], only residues 816 are exposed. Although amyloid aggregates differ substantially in their main sequences, all share common features, such as a high degree of -sheet content material and the capability to bind the heteroaromatic dyes Congo reddish and thioflavin T (ThT) [28]. Theoretically, if all amyloids share a similar -pleated sheet or additional structural features, one may.