SFTI-1

SFTI-1 binds trypsin in a canonical Bowman-Birk inhibitor fashion, inserting the reactive site loop (P1 Lys residue) into the trypsin active site. The cyclic backbone and disulfide bond maintain the ideal geometry of the binding loop complementary to trypsin topology. Unlike linear inhibitors that lose conformational entropy upon binding, SFTI-1 pays minimal entropy cost for binding due to pre-organized structure, explaining its exceptional inhibitor potency relative to its small size.

The SFTI-1 reactive site loop can be substituted with sequences selective for other serine proteases. Matriptase (ST14), KLK-family kallikreins, and FXa have all been targeted with SFTI-1-based scaffolds by substituting the P1 residue and flanking positions. The bicyclic constraint maintains inhibitor potency of engineered variants against targets lacking the original trypsin selectivity. This approach avoids the liabilities of standard peptide drugs (poor stability, oral unavailability).

SFTI-FCQR, an SFTI-1 analog with substituted reactive loop selective for matriptase, inhibits tumor cell invasion in vitro by blocking HGF activation and profilaggrin processing. Matriptase overexpression promotes cancer invasion and metastasis. SFTI-based matriptase inhibitors reduce tumor growth in mouse xenograft models. The stability and selectivity of these bicyclic analogs represent a significant advance over previous matriptase inhibitors.

KLK5, KLK7, and KLK14 are serine proteases involved in skin desquamation and inflammatory skin diseases (atopic dermatitis, Netherton syndrome). SFTI-1 analogs selective for these kallikreins have been developed and show efficacy in skin cell models of inflammatory cascades. The stability of the bicyclic scaffold allows topical application with sustained protease inhibitory activity.