Some regions of nucleic acid targets are not accessible to heteroduplex formation with complementary oligonucleotide probes because they are involved in secondary structure through intramolecular Watson-Crick pairing. In order to form a heteroduplex, we destabilize the secondary conformation of the target to assist its interactions with oligonucleotide probes. To achieve this goal, we modified the DNA target by replacing dC with N-4-ethyldeoxycytidine (d4EtC), which hybridizes specifically with natural dG to give a G4EtC base pair with reduced stability compared with the natural GC base pair. In contrast to its natural analogue, the use of d4EtC greatly minimized the formation of the target's secondary structure in preliminary solution studies. The lower level of secondary structure allowed hybridization with a complementary probe. To characterize further the influence of d4EtC on the stability of secondary structure, hybridization of the targets is currently being studied using an array of complementary oligonucleotides scanning the sequence.