Signal peptide (SP) (SP)

A signal peptide is a short sequence of 16 to 30 amino acids located at the N-terminus of nascent proteins that serves as a molecular tag for intracellular transport [1, 9]. Its primary biological function is to direct nascent polypeptides to the Sec61 translocon on the endoplasmic reticulum membrane for translocation or secretion [5, 6]. While traditionally viewed as a temporary structural motif, the signal peptide has emerged as a novel therapeutic target because its unique primary sequences allow for the selective inhibition of specific protein expression [2]. For example, the small molecule CADA binds to the human CD4 signal peptide, preventing its translocation and thereby reducing surface CD4 levels, which is relevant in HIV and autoimmune research [5, 6]. In addition to direct targeting, the processing of signal peptides by enzymes such as signal peptidase and signal peptide peptidase (SPP) provides further therapeutic opportunities [3, 7]. Inhibiting these enzymes can disrupt the maturation of viral and parasitic proteins, making them viable targets for treating infections like malaria, hepatitis C, and various bacterial diseases [4, 13]. Mutations in signal peptide sequences, often referred to as "signal peptidopathies," are also linked to a range of hereditary disorders and cancers by causing protein mislocalization [10, 12]. Consequently, targeting signal peptides or their processing pathways offers a highly specific approach to modulating the proteome for therapeutic benefit [2, 6].

Other names

Signal sequenceLeader peptideTargeting signalN-terminal leader sequenceProtein sorting signal

Drugs can interact with signal peptides in two primary ways: direct binding to the signal peptide sequence of a specific nascent protein to stabilize a folded conformation that blocks its translocation into the endoplasmic reticulum (e.g., CADA targeting CD4); or inhibition of the processing enzymes signal peptidase (SPase) and signal peptide peptidase (SPP) to prevent the cleavage or clearance of the signal sequence, which disrupts mature protein formation and cellular homeostasis [3, 5, 6, 7].