Instructed-assembly of small peptides inhibits drug-resistant prostate cancer cells

Despite multiple new-drug approvals in recent years, prostate cancer remains a global health challenge because of the prostate cancers are resistant to androgen deprivation therapy. Here, we show that a small D-phosphopeptide undergoes prostatic acid phosphatase (PAP)-instructed self-assembly for inhibiting castration-resistant prostate cancer (CRPC) cells. Specifically, the installation of phosphate at the C-terminal of a D-tripeptide results in the D-phosphopeptide. Dephosphorylating the D-phosphopeptide by PAP forms uniform nanofibers that inhibit VCaP, a CRPC cell. A non-hydrolyzable phosphate analogue of the D-phosphopeptide, which shares similar self-assembling properties with the D-phosphopeptide, confirms that PAP-instructed assembly is critical for the inhibition of VCaP. This work, for the first time, demonstrates PAP-instructed self-assembly of peptides for selective inhibiting CRPC cells.