The synthesis of peptides for both research and API production is conveniently carried out using the solid-phase strategy. However, the main drawback of this approach is the large amounts of hazardous solvents required. In this regard, several pharmaceutical industries participating in the ACS Green Chemistry Institute Pharmaceutical Roundtable have shown interest in identifying green solvents for solid-phase peptide synthesis. In a previous study, our group proposed γvalerolactone (GVL) as a replacement for the hazardous DMF. However, during Fmoc removal of the less hindered Gly residue, acylation with GVL can take place. Here we demonstrate that this side reaction can be circumvented by the incorporation of the corresponding dipeptides that carry Gly as the C-terminal. These dipeptides were conveniently prepared using CTC resin, which can be reused after activation. Using this strategy, GVL proved to be slightly superior to DMF for the synthesis of the demanding ABRF 1992 peptide, which contains five Gly residues.

Graphical superimposed snapshots of the Thompson novel loop (yellow) of menG protein: apo (A) and bound (B) systems. The loop switches between open and closed conformations; critical for therapeutic activity.

No abstract

Mycobacterium tuberculosis (Mtb) encoded secreted antigen 85 enzymes (Ag85A/Ag85B/Ag85C) play that critical roles in the virulence, survival and drug-resistant TB of the pathogen. Ag85 proteins are potential antitubercular drug targets because they are essential in the catalytic synthesis of trehalose moieties and mycolic acid attachment to the Mtb cell wall. Recently, experimental protocols led to the discovery of a selective covalent Ag85 inhibitor, b-isomer monocyclic enolphosphorus Cycliphostin (CyC 8b) compound, which targets the Ag85 serine 124 to exhibit a promising therapeutic activity. For the first time, our study unravelled the structural features among Mtb Ag85C homologs and motions and dynamics of Ag85C when the CyC 8b bound covalently and in open model conformations to the protein using bioinformatics tools and integrated Molecular dynamics simulations. Comparative Ag85C sequence analysis revealed conserved regions; 70% active site, 90% Adeniyi loop L1 and 50% loop L2, which acts as a switch between open and closed conformations. The average C-a atoms RMSD (2.05 Å) and RMSF (0.9 Å) revealed instability and high induced flexibility in the CyC 8b covalent-bound compared to the apo and open model systems, which displayed more stability and lower fluctuations. DSSP showed structural transitions of a-helices to bend and loops to 3 10-helices in the bound systems. SASA of CyC 8b covalent bound showed active site hydrophobic residues exposure to huge solvent. Therefore, these findings present the potential opportunity hotspots in Ag85C protein that would aid the structure-based design of novel chemical entities capable of resulting in potent antitubercular drugs.