The pleiotropic role played by melanocortin
receptors (MCRs) in
both physiological and pathological processes has stimulated medicinal
chemists to develop synthetic agonists/antagonists with improved potency
and selectivity. Here, by deploying the Chemical Linkage of Peptide
onto Scaffolds strategy, we replaced the lactam cyclization of melanotan
II (MT-II), a potent and unselective agonist of human MCRs (hMCRs),
with different xylene-derived thioethers. The newly designed peptides
displayed binding affinities toward MCRs ranging from the low nanomolar
to the sub-micromolar range, highlighting a correlation between the
explored linkers and the affinity toward hMCRs. In contrast to the
parent peptide (MT-II), compound 5 displayed a remarkable
functional selectivity toward the hMC1R. Enhanced sampling molecular
dynamics simulations were found to be instrumental in outlining how
the employed cyclization strategy affects the peptides’ conformational
behavior and, as a consequence, the detected hMC1R affinity. Additionally,
a model of the peptide 5/hMC1R complex employing the
very recently reported cryogenic electron microscopy receptor structure
was provided.
The shelterin component telomeric repeat-binding factor 2 (TRF2) is an essential regulator of telomere homeostasis and genomic stability. Mutations in the TRF2TRFH domain physically impair t-loop formation and prevent the recruitment of several factors that promote efficient telomere replication, resulting in a telomeric DNA damage response. Here, we design, synthesize, and biologically test covalent cyclic peptides that irreversibly target the TRF2TRFH domain. We identify APOD53 as our most promising compound. APOD53 forms a covalent adduct with a reactive cysteine residue present in the TRF2TRFH domain and induces phenotypes consistent with TRF2TRFH domain mutants. These include induction of a telomeric DNA damage response in the absence of fusions, increased telomeric replication stress, and impaired recruitment of regulator of telomere elongation helicase 1 (RTEL1) and structure-specific endonuclease subunit (SLX4) to telomeres. We demonstrate that APOD53 impairs cell growth in both a telomerase-positive and an ALT cell line, while sparing the viability of non-cancerous cells. Finally, we find that co-treatment with APOD53 and the G4 stabilizer RHPS4 further exacerbates telomere replication stress.
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