A structural investigation of FISLE-412, a peptidomimetic compound derived from saquinavir that targets lupus autoantibodies

Bioorg Med Chem Lett. 2017 Oct 15;27(20):4725-4729. doi: 10.1016/j.bmcl.2017.08.070. Epub 2017 Sep 17.

Abstract

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.

Keywords: Anti-DNA antibody; Autoantibodies; Autoimmune; DWEYS; Peptidomimetic; Saquinavir; Structure–Activity Relationship (SAR); Systemic lupus erythematosus (SLE).

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antibodies, Antinuclear / chemistry
  • Antibodies, Antinuclear / metabolism*
  • Drug Design
  • Humans
  • Inhibitory Concentration 50
  • Kidney / metabolism
  • Lupus Erythematosus, Systemic / metabolism
  • Lupus Erythematosus, Systemic / pathology
  • Peptidomimetics
  • Polyamines / chemistry
  • Polyamines / metabolism
  • Quinolines / chemistry*
  • Quinolines / metabolism
  • Saquinavir / chemistry*
  • Structure-Activity Relationship

Substances

  • Antibodies, Antinuclear
  • FISLE-412
  • Peptidomimetics
  • Polyamines
  • Quinolines
  • Saquinavir