Henry R. Wolfe

TUMOR-TARGETING PEPTIDE-PNA-PEPTIDE CHIMERAS FOR IMAGING OVEREXPRESSED ONCOGENE mRNAS

We have optimized a method involving continuous solid phase synthesis of chelator-peptide-PNA-peptide probes in order to noninvasively image oncogene mRNAs overexpressed in tumors. The PNA (peptide nucleic acid) probes carry cyclized peptide ligand analogs specific for receptors overexpressed on malignant breast or colorectal cancer cells, and chelators to bind radioactive metal ions, or a fluorophore. In vivo scintigraphic imaging of MCF7 xenografts in immunocompromised mice indicated that CCND1 and MYC [99mTc]chelator-PNA-D(CSKC) probes concentrated in MCF7 cells up to 7 times more than the corresponding mismatch controls.

STa peptide analogs for probing guanylyl cyclase C

Guanylyl cyclase C (GC‐C), universally overexpressed on primary and metastatic colorectal carcinoma cells, is activated by endogenous ligands, guanylin, and uroguanylin, and by exogenous 18‐residue heat‐stable enterotoxins (STa) produced by diarrheagenic bacteria. Two 12‐residue STa analogs with alternate combinations of two interlocked disulfide bonds, peptides 3 and 6, were synthesized by orthogonal solid phase synthesis routes. Peptides 3 and 6 bound GC‐C with a rank order potency of STa > peptide 3 > peptide 6. Peptides 3 and 6 behaved as agonists in stimulating cGMP production. The results reveal that the toxic domain of STa can be reduced to 12 amino acids.