We also observed that peptide treated cells varied greatly in DNA content as judged from microscopic studies. These observations are in agreement with uncoupling of leading and lagging strand synthesis which result in failure to complete chromosome replication which may, by segregation failure, explain the appearance of DNA less cells as well as cells containing an increased amount of DNA. A further contribution to the latter could be the occurrence of damage induced DNA replication triggered by strand breaks. Strand breaks as a result of DnaN inhibition may be sufficient to explain why peptides are bacteriocidal upon prolonged exposure. This situation may be parallel to that elicited by gyrase inhibitors such as ciprofloxacin which trap the gyrase molecule at the DNA cleavage stage and eventually result in formation of double stranded breaks. Clearly the potency of our first generation of peptides targeting the b-clamp of Gram positive bacteria is too poor for direct testing as new antimicrobials. However they may still serve as lead compounds on the way to identify more efficient versions, for example by Quantitative Structure-Activity Relationship modeling, to relate RQ-00000007 cost structural characteristics of the peptides to biological activity. A key question is whether their limited activity results from poor entry into bacterial cells, poor interaction with their target or both. It is also our hope that these peptides along with others that target other key interactions between replication proteins will turn out as useful tools for studying DNA replication in vivo. Glioblastoma multiforme is the most common and aggressive brain tumor in humans and despite technical advances in neurosurgery and clinical neuro-oncology, the prognosis for GBM patients remains very poor. Most patients die within one year of diagnosis and are generally insensitive to current therapeutic genotoxic interventions. In the majority of GBM cases, resistance to such genotoxic modalities has been attributed to the attenuation of p53 function by alterations within the p53 signalling axis, including the overexpression of Murine Double Minute-2. The MDM2 oncoprotein, a major physiological negative regulator of p53, can bind to the p53 transactivation domain and 160098-96-4 interfere with the transcriptional regulatory mechanisms of p53. MDM2 is also an E3 ubiquitin ligase that promotes p53 proteasomal degradation. For this reason, inhibition of the interaction between MDM2 and p53 to reactivate endogenous p53 activity offers the opportunity for therapeutic intervention, particularly in GBMs.
