Thimmalapura Marulappa Vishwanatha

PhD

Postdoc

Bioconjugation Medicinal Chemistry Multi-step organic synthesis

1st author preprint(s) Conference Poster(s) Conference Talks(s)

I contributed to the accelerating drug discovery projects through automated chemical synthesis and miniaturized high-throughput methodologies. I design novel synthetic strategies for macrocyclic peptides enabling rapid library generation in 96, 384 and 1536 well formats. My work includes developing and optimizing new chemistries—such as amide bond formation, macrocyclization, multicomponent reactions, and post-synthetic modifications—to produce diverse molecular libraries. Further, I use dedicated high throughput LCMS instrument to analyze those libraries and quantify and purify them in small scale for evaluation in desired biological targets. Additionally, I also work on multistep synthesis projects involving tubulysin payload and linker chemistry for collaborative studies on antibody drug conjugates.

developed covalent compound libraries using Echo-assisted nanoscale synthesis in 96-, 384-, and 1536-well formats. These libraries were analyzed by LC–MS and directly used for high-throughput biochemical screening against deubiquitinating enzymes (DUBs). Hit compounds were cherry-picked, resynthesized in parallel, and evaluated for potency and selectivity. I further contributed to multistep organic synthesis projects involving peptide-based fluorescent probes and the preparation of unnatural amino acids.

My main project involved synthesizing macrocyclic analogs of the neuropeptide kisspeptin-10 (KP10) to improve proteolytic stability, potency, and receptor selectivity. I developed an innovative late-stage solid-phase macrocyclization strategy based on bis-electrophile-mediated thiol coupling, systematically introducing pairs of Cys, residues (D- or L-, i/i+3 to i/i+7). The resulting macrocycles were purified by HPLC and further conjugated with modified with PEG and albumin-binding motifs for in vivo evaluation in mice. Additionally, I optimized Fmoc-SPPS protocols, developed palladium-mediated thioglycosylation of iodoaryl peptides, and incorporated amide-bond surrogates such as aza and triazole moieties. During the fellowship, I also developed a novel chemo selective inverse-peptide ligation reaction between unprotected peptide thioacids and peptidyl imidazolyl urea’s and bioconjugation of peptides through N-terminal serine oxidation.