Chemistry Reference
In-Depth Information
diffusible radicals upon DNA cleavage is undesirable when designing an artifi cial
nuclease bearing high sequence selectivity.
Often, a hydrolytic rather than an oxidative cleavage mechanism is desirable
for several reasons. Production of diffusible free radicals by oxidative cleavage of
DNA results in strand ends that cannot be enzymatically religated in molecular
biology applications. For clinical applications, oxidative cleavage can cause
indiscriminate peripheral damage to the cell while radical diffusion may affect signi-
fi cantly the specifi city of cleavage that can be achieved.
15
Rh(III) metallointercalator -
Zn(II) metallopeptide conjugates are the only chimeric molecules utilizing a
hydrolytic mechanism of cleavage (Table 12.2). The pseudo fi rst - order rate constant
of [Rh(phi)
2
(bpy
10
− 5
s
− 1
)
54
determined for plasmid DNA degrada-
tion is of the same magnitude to the bimetallic Zn(II)
2
- heptapeptide developed by
P. Scrimin
et al.
58
and to lanthanide metallopeptides.
60
Therefore, conjugation of a
Rh(III) metallointercalator to a hydrolytically active Zn(II) metallopeptide appears
to be an effective system for the hydrolysis of DNA, displaying moderate sequence
selectivity.
54
The versatility of such systems could probably meet the requirements
for obtaining the desired hydrolytic activity in the near future.
′
) - P1+Zn(II) (1
×
12.5
Conclusion
By careful design of transition metal complex-peptide conjugates, specifi c recogni-
tion of a DNA site may be achieved, which in some cases can be perturbed by a
single amino acid modifi cation. However, there are some limitations for the recogni-
tion of a DNA-binding protein cognate sequence by a peptide model of the native
protein. In this case, issues of peptide fl exibility need to be addressed. Indeed, highly
structured appended peptides provide a higher degree of specifi city for DNA rec-
ognition. DNA specifi c recognition is often accompanied by signifi cant nucleolytic
activity. Transition metal complex-peptide conjugates are not as effi cient in DNA
cleavage as metal-coordinated peptides. The reason probably lies in the different
mechanism employed in each case. However, appropriately designed appended
peptides may result in signifi cant DNA hydrolytic activity by delivering Zn(II) ions
to the DNA phosphate backbone. Importantly, metal complex-peptide conjugates
are able to interact with the DNA major groove, commonly exploited upon DNA
recognition by DNA-binding proteins. The versatility of these systems has become
evident, thus further enhancement of their DNA recognition and cleavage proper-
ties may be achieved by appropriate selection of the ancillary ligands, the peptide
composition and the metal ion.
Abbreviations
AP1
Activator protein
bpy
2,2
′
- Bipyridine
