Sphingamide compounds and methods for binding iNKT cells

Inventors

Zajonc, Dirk • Van Calenbergh, Serge • Elewaut, Dirk • Guillaume, Joren

Assignees

Universiteit Gent • Vlaams Instituut voor Biotechnologie VIB • La Jolla Institute for Allergy and Immunology

Abstract

The compounds, compositions and methods provided herein antagonize, inhibit, decrease, reduce, suppress, or disrupt CD1d-mediated, iNKT cell-mediated, and/or iNKT cell TCR-mediated immune signaling. The sphingamide compounds were rationally designed based upon 3D structural considerations in relation to the structures of each of CD1d, the iNKT cell TCR, and the ternary complex CD1d-a-GalCer analog lipids-TCR. More specifically, the addition of an amide in the phytosphingosine tail of a derivative of α-GalCer led to a non-conserved binding with CD1d, a conserved binding with the iNKT cell TCR, and an antagonist-like phenotype.

Core Innovation

The invention relates to compounds of formula I, including pharmaceutically acceptable salts, prodrugs, and pharmaceutically acceptable salts thereof, defined by specific structural features of the sphingamide scaffold. The compounds include an alkyl chain X having 3 to 30 carbons with at least one intervening amide group terminating in a phenyl group or a terminating alkyl substituted anilide, an alkyl chain Y having 5 to 30 carbons, Z as OH, and L as an oxygen atom or a C-glycoside analogue thereof.

A key aspect is immunology-focused binding and functional characterization of the sphingamide compounds to CD1d and iNKT cell TCR. The disclosed content includes CD1d binding and iNKT cell TCR binding, and the binding mode is described as non-conserved versus α-GalCer, with hydrogen-bonding residue differences and formation of an additional hydrogen bond in a ternary complex context comprising CD1d, the sphingamide compound, and the iNKT TCR.

The invention further characterizes immune-modulating activity and categorizes behavior as agonist, inverse agonist, or antagonist activity. The disclosed content describes immune response modulation through cytokines including IL-2, IFN-γ, IL-4, TNF-α, IL-12, and GM-CSF, and includes binding affinity ranges, SPR kinetics, and crystallography statements describing ternary complex-induced sphingamide headgroup repositioning and associated structural interactions.

Claims Coverage

The claim coverage centers on one independent compound claim defining formula I and its pharmaceutically acceptable salts, with additional dependent claim refinements that specify biological binding targets, constrain binding behavior relative to α-GalCer, and add quantitative binding-affinity constraints, together with optional further chemical tightening through substituent definition for Y. Across the claim set, six inventive features are identified.

Overall, the claim set focuses on formula I sphingamide/α-GalCer analog compounds defined by X, Y, Z, and L, and further narrows coverage by specifying CD1d and iNKT cell TCR binding, a human SEQ ID NO: 4 or substantially identical CD1d sequence, a non-conserved binding phenotype relative to α-GalCer, and nanomolar binding-affinity constraints.

Stated Advantages

Documented Applications