Enhancing the Drug-Like Profile of a Potent Peptide PACE4 Inhibitor by the Formation of a Host-Guest Inclusion Complex with beta-Cyclodextrin

The enzyme PACE4 has been validated as a promising therapeutic target to expand the range of prostate cancer (PCa) treatments. In recent years, we have developed a potent peptidomimetic inhibitor, namely, compound C23 (Ac-(DLeu)LLLRVK-4-amidinobenzylamide). Like many peptides, C23 suffers from an unfavorable drug-like profile which, despite our efforts, has not yet benefited from the usual SAR studies. Hence, we turned our attention toward a novel formulation strategy, i.e., the use of cyclodextrins (CDs). CDs can benefit compounds through the formation of host-guest complexes, shielding the guest from degradation and enhancing biological survival. In this study, a series of beta CD-C23 complexes have been generated and their properties evaluated, including potency toward the enzyme in vitro, a cell-based proliferation assay, and stability in plasma. As a result, a new beta CD-formulated lead compound has been identified, which, in addition to being more soluble and more potent, also showed an improved stability profile.

Automated summary

The use of cyclodextrins (CDs) as drug carriers has been found to improve the unfavorable characteristics and enhance the stability of the anticancer drug C23.