Compositions and methods for treating CD40-mediated diseases
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Publication Number
US-12522633-B2
Publication Date
2026-01-13
Expiration Date
Abstract
A cell-penetrating peptide includes a membrane transduction domain linked to a CD40-TRAF2,3 blocking peptide that includes an amino acid sequence substantially identical to the amino acid sequence of the TRAF2,3 binding domain to CD40 or a retro-inverso amino acid sequence thereof.
Core Innovation
The invention relates to compositions for inhibiting CD40-mediated inflammatory diseases by using a cell-penetrating peptide linked to a CD40-TRAF2,3 blocking peptide. The blocking peptide competitively inhibits binding of TRAF2 to the TRAF2,3 binding domain while preserving CD40L binding. The design explicitly excludes the amino acid sequence PVQET (SEQ ID NO: 10) and also excludes retro-inverso amino acid sequences thereof.
The compositions comprise a cell-penetrating peptide that includes a membrane transduction domain linked to a CD40-TRAF2,3 blocking peptide. The blocking peptide comprises a polypeptide having an amino acid sequence of SEQ ID NO: 9 or a retro inverso amino acid sequence thereof, with additional positional constraints on X1, X2, and X3 residues.
The provided embodiments report that retro-inverso CD40-TRAF2,3 blocking peptide penetrates retinal cells and selectively inhibits CD40-TRAF2,3 signaling without targeting CD40-TRAF6 signaling. The resulting outcomes include reduced upregulation of inflammatory mediators, reduced leukocyte infiltration, and reduced neuronal/ganglion cell layer loss after retinal ischemia/reperfusion, while not impairing toxoplasma gondii control.
Claims Coverage
The partial content includes two independent composition claims. The claims cover a cell-penetrating peptide linked to a CD40-TRAF2,3 blocking peptide that competitively inhibits TRAF2 binding to the CD40 TRAF2,3 binding domain, with sequence exclusions and SEQ ID NO: 9 or retro-inverso inclusion constraints.
Cell-penetrating peptide with linked membrane transduction domain and CD40-TRAF2,3 blocking peptide
A composition comprising a cell-penetrating peptide that includes a membrane transduction domain linked to a CD40-TRAF2,3 blocking peptide that competitively inhibits binding of TRAF2 to the TRAF2,3 binding domain.
Blocking peptide excludes PVQET while preserving CD40-TRAF2,3 competitiveness
The CD40-TRAF2,3 blocking peptide does not include the amino acid sequence of PVQET (SEQ ID NO: 10) or a retro-inverso amino acid sequence thereof and comprises a polypeptide having an amino acid sequence of SEQ ID NO: 9 or a retro inverso amino acid sequence thereof.
Sequence constraints on X1/X2/X3 residues for the blocking peptide
The CD40-TRAF2,3 blocking peptide comprises a polypeptide in which X1 is not P if X2 is V and X3 is T; X2 is not V if X1 is P and X3 is T; and X3 is not T if X1 is P and X2 is V.
Competitively inhibits TRAF2 binding to CD40 TRAF2,3 binding domain of cells
A composition comprising a cell-penetrating peptide that competitively inhibits binding of TRAF2 to the TRAF2,3 binding domain of CD40 of cells.
Membrane transduction domain linked to CD40-TRAF2,3 blocking peptide with PVQET exclusion
The cell-penetrating peptide comprises a membrane transduction domain linked to a CD40-TRAF2,3 blocking peptide wherein the CD40-TRAF2,3 blocking peptide does not include the amino acid sequence of PVQET (SEQ ID NO: 10) or a retro-inverso amino acid sequence thereof.
Blocking peptide sequence defined as SEQ ID NO: 9 (or retro inverso) with X1/X2/X3 constraints
The CD40-TRAF2,3 blocking peptide comprises a polypeptide having an amino acid sequence of SEQ ID NO: 9 or a retro inverso amino acid sequence thereof, wherein X1 is not P if X2 is V and X3 is T; X2 is not V if X1 is P and X3 is T; and X3 is not T if X1 is P and X2 is V.
Across both independent claims, the core coverage is the same: a cell-penetrating peptide with a membrane transduction domain linked to a CD40-TRAF2,3 blocking peptide that competitively inhibits TRAF2 binding to the CD40 TRAF2,3 binding domain. The claims further constrain the blocking peptide by excluding PVQET (SEQ ID NO: 10) and retro-inverso versions, while requiring inclusion of SEQ ID NO: 9 (or retro-inverso) with specified X1/X2/X3 positional constraints.
Stated Advantages
Retro-inverso CD40-TRAF2,3 blocking peptide selectively inhibits CD40-TRAF2,3 signaling without inhibiting CD40-TRAF6 signaling.
Reduced upregulation of pro-inflammatory mediators including ICAM-1, CXCL1/CCL2, NOS2/COX-2, TNF-α, and IL-1β.
Diminishes leukocyte infiltration.
Reduces neuronal/ganglion cell layer loss after retinal ischemia/reperfusion.
Does not impair toxoplasma gondii control.
Documented Applications
Treatment of CD40-mediated inflammatory diseases, including use evaluated in a retinal ischemia/reperfusion context with effects on retinal injury and leukocyte infiltration.
Infectious retinitis context used for comparison, where ri CD40-TRAF6 blocking peptide worsens infectious retinitis and affects systemic IL-12 p70/dendritic cell activation.
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