The signal peptide as a new target for drug design

Abstract

Many current and potential drug targets are membrane-bound or secreted proteins that are expressed and transported via the Sec61 secretory pathway. They are targeted to translocon channels across the membrane of the endoplasmic reticulum (ER) by signal peptides (SPs), which are temporary structures on the N-termini of their nascent chains. During translation, such proteins enter the lumen and membrane of the ER by a process known as co-translational translocation. Small molecules have been found that interfere with this process, decreasing protein expression by recognizing the unique structures of the SPs of particular proteins. The SP may thus become a validated target for designing drugs for numerous disorders, including certain hereditary diseases.

Keywords: CADA; CD4; ER; Hereditary diseases; Inhibitor; Protein; Sec61; Signal peptide; Sortilin; Translocation.

Fig. 1

Co-translational translocation of Type I transmembrane proteins across the ER membrane. 1: SRP transfers RNC to the translocon via the SRP receptor (not shown). 2: SP binds to hydrophobic pocket of the lateral gate. 3: translation continues, the SP inverts. 4: translation continues, the SP binds fully to the lateral gate. 5: SP is cleaved by SPase. 6: as a hydrophobic transmembrane domain emerges, it binds to the lateral gate. 7: translation ends, the ribosome departs, and the protein moves into the ER membrane.

Fig. 2

Structures of co-translational translocation inhibitors CAM741, cotransin, and CADA.

Fig. 3

Dose-response curves for down-modulation of sortilin vs. CD4.

Fig. 4

Proposed mechanism for inhibition of CD4 co-translational translocation across the ER membrane. 1: SRP binds to signal receptor (not shown) and transfers RNC to the translocon. 2: SP binds to hydrophobic pocket of the lateral gate. 3: as translation continues, CADA binds to the SP and stabilizes a folded conformation, halting translocation. 4: as translation continues, the elongating protein chain loops into the cytosol and is degraded by proteolytic enzymes.

Fig. 5

Potencies of compounds bearing electron donating (red) or electron withdrawing groups (blue). IC₅₀ = concentration giving 50% CD4 downmodulation. Inset: correlation between potency and side arm dipole moment.