ShK-186 is poorly immunogenic and did not elicit anti-ShK antibodies in rats repeatedly administered the peptide. This is possibly because the peptide's disulfide-bonded structure hinders processing and antigen presentation by antigen-presenting cells. ShK-186 also shares sequence and structural similarity to a ShK-like domain in matrix metalloprotease 23, which may cause the immune system to assume it is a normal protein in the body. ShK-186 was safe in non-human primates. In Phase 1a and 1b trials in healthy human volunteers, ShK-186 was well tolerated, no grade 3 or 4 adverse effects or laboratory abnormalities were noted, and the predicted range of drug exposures were achieved. The most common adverse events were temporary mild (Grade 1) hypoesthesia and paresthesia involving the hands, feet, or perioral area. Mild muscle spasms, sensitivity of teeth, and injection site pain were also observed. MMP-23 belongs to the family of zinc- and calcium-dependent matrix metalloproteases. It is anchored in the cell membrane by an N-terminal prodomain, and it contains three extracellular domains: catalytic metalloprotease domain, ShK domain and immunoglobulin-like cell adhesion molecule (Ig-CaM) domain. The prodomain traps the voltage-gated potassium channel KV1.3, but not the closely related KV1.2 channel, in the endoplasmic reticulum. Studies with chimeras suggest that the prodomain interacts with the KV1.3 region from the S5 transmembrane segment to the C terminus. NMR studies of the prodomain reveal a single trans-membrane alpha-helix, joined by a short linker to a juxta-membrane alpha-helix, which is associated with the surface of the membrane. The prodomain shares topological similarity with proteins (KCNE1, KCNE2, KCNE4) known to trap potassium channels in the secretory pathway, suggesting a shared mechanism of channel regulation. MMP-23's catalytic domain displays structural homology with catalytic domains in other metalloproteases, and likely functions as an endopeptidase. MMP-23's ShK domain lies immediately after the catalytic domain and is connected to the IgCAM domain by a short proline-rich linker.