<b>Part I: Solid - phase synthesis of peptides using photolabile linkers</b><b>Part II: Discovery of lead compounds by fragment screening to target pathogenic Gram-positive bacteria</b>

<h2><a href="" target="_blank">Part 1: Solid-phase synthesis of peptides using photolabile linkers</a></h2><p dir="ltr">One of the major limitations of traditional native chemical ligation (NCL) of peptides is its dependence on cysteine residue. This amino acid is one of the least abundant one which limits its utility in NCL reactions. Auxiliary mediated NCLs are a solution to this problem, however, they are either difficult to remove or they decrease reactivity of the ligated peptides. The Lipton Lab developed two photolabile auxiliaries that use a nitro group <i>ortho </i>to a benzyl group to perform photocleavage by undergoing Norrish type II reaction. Other features of the auxiliaries include having a benzyl thiol that transesterifies with the N-peptide, does an S- to O- acyl transfer followed by an O- to N- acyl transfer to carry out ligation reactions. These linkers were first used to make dipeptides and then tested to synthesize decapeptides. These linkers have improved the scope of ligation reactions using amino acid residues such as Gly, Ala and Leu in the N-peptides.</p><p dir="ltr">Backbone amide linkers are molecules that are attached to the amide backbone leaving the N-terminus available for peptide elongation and the C-terminus accessible for any modification. However, most BALs are sensitive to acids and can be taken off resin when acid-sensitive protecting groups for functional sidechains are being deprotected. The Lipton Lab developed a photolabile backbone amide linker that addresses the issue of acid-sensitivity by introducing another dimension of orthogonality (in addition to acid sensitivity, base sensitivity and sensitivity towards Pd⁰)using UV light to cleave a synthesized peptide off the resin once a sequence has been made. This photolabile linker was used to first synthesize dipeptides in solution and then applied into synthesizing cyclic peptides and peptide thioesters to demonstrate its versatility.</p><h2><a href="" target="_blank">Part 2: Discovery of new leads against pathogenic Gram-positive bacteria by fragment-based screening</a></h2><p dir="ltr">Most antibacterials that are commercially available are modifications of already existing drugs or target the same enzymes that bacteria have already developed resistance towards. HMG CoA reductase is a new attractive target against pathogenic Gram-positive bacteria. This enzyme found is involved in the mevalonate pathway that synthesizes isopentenyl pyrophosphate, an important material for bacterial survival. In collaboration with the Stauffacher laboratory at Purdue University and the Southern Research Institute in Birmingham, Alabama, a lead compound was identified by high-throughput screening. After multiple generations of new designs and synthesis based on this lead, our inhibitors show promising enzyme inhibition but poor antibacterial activity. Also, the lead generated in this study had limited avenues of modification and resulted in inhibitors that were not drug-like. We use a fragment-based screening approach to identify new leads. After screening 3,600 fragments, 42 hits were identified. These hits were further studied, and we found good inhibition data from 22 fragments. The molecules are currently being co-crystallized with our protein of interest such that we can study their binding modes, design and synthesize new inhibitors with better potency.</p>