Extensive targeting of chemical space at the prime side of ketoamide inhibitors of rhomboid proteases by branched substituents empowers their selectivity and potency.

Rhomboid intramembrane serine proteases have been implicated in several pathologies, and emerge as attractive pharmacological target candidates. The most potent and selective rhomboid inhibitors available to date are peptidyl α-ketoamides, but their selectivity for diverse rhomboid proteases and strategies to modulate it in relevant contexts are poorly understood. This gap, together with the lack of suitable in vitro models, hinders ketoamide development for relevant eukaryotic rhomboid enzymes. Here we explore the structure-activity relationship principles of rhomboid inhibiting ketoamides by medicinal chemistry and enzymatic in vitro and in-cell assays with recombinant rhomboid proteases GlpG, human mitochondrial rhomboid PARL and human RHBDL2. We use X-ray crystallography in lipidic cubic phase to understand the binding mode of one of the best ketoamide inhibitors synthesized here containing a branched terminal substituent bound to GlpG. In addition, to extend the interpretation of the co-crystal structure, we use quantum mechanical calculations and quantify the relative importance of interactions along the inhibitor molecule. These combined experimental analyses implicates that more extensive exploration of chemical space at the prime side is unexpectedly powerful for the selectivity of rhomboid inhibiting ketoamides. Together with variations in the peptide sequence at the non-prime side, or its non-peptidic alternatives, this strategy enables targeted tailoring of potent and selective ketoamides towards diverse rhomboid proteases including disease-relevant ones such as PARL and RHBDL2.

Mg Doping of N-Polar, In-Rich InAlN.

Metal organic chemical vapor deposition was used to grow N-polar In0.63Al0.37N on sapphire substrates. P-doping was provided by a precursor flow of Cp2Mg between 0 and 130 nmol/min, reaching a Cp2Mg/III ratio of 8.3 × 10-3. The grain structure of 360 nm thick InAlN was spoiled by pits after introducing a flow of CP2Mg at 30 nmol/min. The surface quality was improved with a flow of 80 nmol/min; however, detrimental deterioration appeared at 130 nmol/min. This correlated with the XRD shape and determined density of dislocations, indicating a phase separation at the highest flow. Degenerated n-type conduction and a free carrier concentration of ~1019 cm-3 were determined in all samples, with a minor compensation observed at a CP2Mg flow of 30 nmol/min. The room temperature (RT) electron mobility of ~40 cm2/Vs of the undoped sample was reduced to ~6 and ~0.3 cm2/Vs with a CP2Mg flow of 30 and 80 nmol/min, respectively. Scattering at ionized acceptor/donor Mg-related levels is suggested. RT photoluminescence showed a red shift of 0.22 eV from the virgin 1.73 eV peak value with Mg doping. Mobility degradation was found to be the main factor by InAlN resistivity determination, which increased by two orders of magnitude, approaching ~0.5 Ωcm, at the highest Cp2Mg flow.

In(Ga)N 3D Growth on GaN-Buffered On-Axis and Off-Axis (0001) Sapphire Substrates by MOCVD.

In(Ga)N epitaxial layers were grown on on-axis and off-axis (0001) sapphire substrates with an about 1100 nm-thick GaN buffer layer stack using organometallic chemical vapor deposition at 600 °C. The In(Ga)N layers consisted of a thin (~10-25 nm) continuous layer of small conical pyramids in which large conical pyramids with an approximate height of 50-80 nm were randomly distributed. The large pyramids were grown above the edge-type dislocations which originated in the GaN buffer; the dislocations did not penetrate the large, isolated pyramids. The large pyramids were well crystallized and relaxed with a small quantity of defects, such as dislocations, preferentially located at the contact zones of adjacent pyramids. The low temperature (6.5 K) photoluminescence spectra showed one clear maximum at 853 meV with a full width at half maximum (FWHM) of 75 meV and 859 meV with a FWHM of 80 meV for the off-axis and on-axis samples, respectively.