Improving binding affinity through cyclization

Cancer chemotherapy results in systematic damage as the drugs used are also toxic to benign tissue. Sensitizing a cancer cell to therapy by interfering with the DNA repair mechanisms would decrease overall toxicity, as the necessary dosage of chemotherapy drugs would be lowered. The Hartman lab developed a peptide (8.6) that binds with a KD of 1 μM to the C-terminal domain of breast cancer associated protein (BRCA1), blocking homologous recombination. The crystal structure of the peptide shows the tyrosine and threonine residues are close together, suggesting that by cyclizing these positions, the peptide may already be constrained into its bound conformation. A series of dibromomethylnaphthalene linkers of various length were synthesized and cyclized through alkylation of the cysteine residues on peptide 8.6. The binding of the cyclic peptides with the BRCA1 (BRCT)2 domain will be compared to peptide 8.6 through the use of fluorescence polarization.https://scholarscompass.vcu.edu/uresposters/1248/thumbnail.jp

Biomechanics of Nested Transforaminal Lumbar Interbody Cages.

BACKGROUND: Arthrodesis is optimized when the structural graft occupies most of the surface area within a disc space. The transforaminal corridor inherently limits interbody size. OBJECTIVE: To evaluate the biomechanical implications of nested interbody spacers (ie, a second curved cage placed behind a first) to increase disc space coverage in transforaminal approaches. METHODS: Seven lumbar human cadaveric specimens (L3-S1) underwent nondestructive flexibility and axial compression testing intact and after transforaminal instrumentation at L4-L5. Specimens were tested in 5 conditions: (1) intact, (2) interbody, (3) interbody plus bilateral pedicle screws and rods (PSR), (4) 2 nested interbodies, and (5) 2 nested interbodies plus PSR. RESULTS: Mean range of motion (ROM) with 1 interbody vs 2 nested interbodies, respectively, was: flexion, 101% vs 85%; extension, 97% vs 92%; lateral bending, 127% vs 132%; and axial rotation, 145% vs 154%. One interbody and 2 nested interbodies did not differ significantly by loading mode (P \u3e .10). With PSR, ROM decreased significantly compared with intact, but not between interbody and interbody plus PSR or 2 interbodies plus PSR (P \u3e .80). Mean vertical height during compressive loading (ie, axial compressive stiffness) was significantly different with 2 nested interbodies vs 1 interbody alone (P \u3c .001) (compressive stiffness, 89% of intact vs 67% of intact, respectively). CONCLUSION: Inserting a second interbody using a transforaminal approach is anatomically feasible and nearly doubles the disc space covered without affecting ROM. Compressive stiffness significantly increased with 2 nested interbodies, and foraminal height increased. Evaluation of the clinical safety and efficacy of nested interbodies is underway