FISLE-412 is the first reported small molecule peptidomimetic that neutralizes anti-dsDNA autoantibodies associated with systemic lupus erythematosus (SLE) pathogenesis. FISLE-412 is a complex small molecule that involves a challenging synthesis scheme, but has attractive pharmacological activities as a potential small molecule therapeutic in lupus. Therefore, we initiated a Structure–Activity Relationship study to simplify the complexity of FISLE-412. We synthesized a small library of mimetopes around the FISLE-412 structure and identified several analogues which could neutralize anti-DNA lupus antibodies in vitro and ex vivo. Our strategies reduced the structural complexity of FISLE-412 and provide important information that may guide development of potential autoantibody-targeted lupus therapeutics.

FISLE-412 是第一个报道的小分子拟肽，可中和与系统性红斑狼疮 (SLE) 发病机制相关的抗 dsDNA 自身抗体。FISLE-412 是一种复杂的小分子，涉及具有挑战性的合成方案，但作为一种潜在的狼疮小分子治疗剂具有诱人的药理活性。因此，我们启动了一项构效关系研究，以简化 FISLE-412 的复杂性。我们在 FISLE-412 结构周围合成了一个小型模拟表位库，并鉴定了几种可以在体外和体外中和抗 DNA 狼疮抗体的类似物. 我们的策略降低了 FISLE-412 的结构复杂性，并提供了可能指导开发潜在的自身抗体靶向狼疮疗法的重要信息。