Polypurine reverse Hoogsteen (PPRH) molecules are DNA hairpins formed by two
polypurine strands running in an antiparallel orientation and containing no nucleotide modifications.
The two strands, linked by a pentathymidine loop, are bound through intramolecular
reverse Hoogsteen bonds. Then, PPRHs can bind by Watson-Crick bonds to their corresponding
polypyrimidine target in the dsDNA provoking a displacement of the polypurine strand of
the duplex. We described the effect and mechanisms of action of PPRHs in cells using PPRHs
designed against the template and coding strands of the dhfr gene. The proof of principle of
PPRHs as a therapeutic tool was established using a PPRH against survivin in a xenograft
prostate cancer tumor model. To improve the PPRHs effect, the influence of the length was
studied obtaining a higher efficiency with longer molecules. To decrease the possible offtarget
effect, when a purine interruption is found in the pyrimidine target, the PPRH sequence
should contain both strands of the complementary base opposite to the interruption. Furthermore,
the stability of PPRHs is higher than that of siRNAs, as evidenced by the longer halflife
of the former in different types of serum and in PC3 cells. PPRHs do not induce the levels
of the transcription factors nor the proinflammatory cytokines involved in the Toll-like Receptor
pathway and they do not trigger the formation of the inflammasome complex. PPRHs
can be used as therapeutic tools to target genes related to cancer progression, resistance to
drugs or immunotherapy approaches.
Keywords: PPRHs, cancer, gene silencing, Hoogsteen bonds, apoptosis, stability, immunotherapy.
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