Indraneel Ghosh
Professor, BIO5 Institute
Professor, Chemistry and Biochemistry-Sci
Primary Department
Department Affiliations
(520) 621-6331
Work Summary
The broad objective of our research program in Bioorganic Chemistry and Chemical Biology is to construct protein therapeutics, protein mimetics, biomaterials, and biosensors. Our research at the University of Arizona is highly multidisciplinary and utilizes techniques in organic synthesis, biochemistry, molecular biology, and a host of physical characterization methods. Our research motto is simple: Unraveling mysteries and Enabling discoveries.
Research Interest
Professor Neel Ghosh, is the Emily Davis and Homer Weed Distinguished Professor ’08 at the University of Arizona. His laboratory is broadly interested in Chemical Biology and Protein Design and Engineering with a focus on developing new tools and methods for advancing human health. The laboratory has a particular current interest in understanding protein kinases and protein-protein interactions and designing new ways to inhibit them in human diseases. Neel Ghosh is also a co-founder and Chief Scientific Officer for Luceome Biotechnologies. Neel received his doctoral degree in 1998 while working with Professor Jean Chmielewski at Purdue University. His doctoral research focused on designing inhibitors of protein-protein interactions and self-replicating peptides. In 1998 he joined Professor Andrew Hamilton and Professor Lynne Regan’s laboratories at Yale University as a joint postdoctoral fellow. At Yale, he discovered the first conditional split-Green Fluorescent Protein, which has been used as a means for measuring protein-protein interactions by many laboratories and the methodology is sometimes called fluorescent protein complementation. In 2001, Neel Ghosh joined the Department of Chemistry and Biochemistry at the University of Arizona as an Assistant Professor and was promoted to Associate Professor and then to the Davis & Weed Chair and Full Professor in 2011. Keywords: Chemistry, Biochemistry, Biomedical Engineering, Cancer


Meyer, S. C., Huerta, C., & Ghosh, I. (2005). Single-site mutations in a hyperthermophilic variant of the B1 domain of protein G result in self-assembled oligomers. Biochemistry, 44(7), 2360-2368.

PMID: 15709748;Abstract:

We have characterized two homologous, single-point core mutants of a 57-residue, hyperthermophilic variant of the B1 domain of protein G (HTB1). These single-point mutations in HTB1 replace a Phe residue in the hydrophobic core with either a Glu or Asp residue. Both of these homologous core-variant mutants undergo significant structural rearrangement from the native, monomeric fold and exist as stable soluble oligomeric species of 5 and 30 nm in diameter. Gel-filtration, dynamic light scattering, circular dichroism spectroscopy, fluorescence spectroscopy, along with Congo Red and Thioflavin T binding clearly demonstrated that these core-variants undergo significant structural rearrangement from the native, monomeric ubiquitin fold. The two oligomeric species did not equilibrate over extended periods of time and displayed distinct secondary structures. The larger of the two species was found to possess structural features that are reminiscent of an emerging class of protein assemblies prone to β-sheet-mediated aggregation. These results are significant as there are very few examples of extensive conformational or oligomerization switching brought about by single-point mutations in a stable protein-fold.

Ghosh, I., Lamba, V., & Ghosh, I. -. (2012). New directions in targeting protein kinases: focusing upon true allosteric and bivalent inhibitors. Current pharmaceutical design, 18(20).

Over the past decade, therapeutics that target subsets of the 518 human protein kinases have played a vital role in the fight against cancer. Protein kinases are typically targeted at the adenosine triphosphate (ATP) binding cleft by type I and II inhibitors, however, the high sequence and structural homology shared by protein kinases, especially at the ATP binding site, inherently leads to polypharmacology. In order to discover or design truly selective protein kinase inhibitors as both pharmacological reagents and safer therapeutic leads, new efforts are needed to target kinases outside the ATP cleft. Recent advances include the serendipitous discovery of type III inhibitors that bind a site proximal to the ATP pocket as well as the truly allosteric type IV inhibitors that target protein kinases distal to the substrate binding pocket. These new classes of inhibitors are often selective but usually display moderate affinities. In this review we will discuss the different classes of inhibitors with an emphasis on bisubstrate and bivalent inhibitors (type V) that combine different inhibitor classes. These inhibitors have the potential to couple the high affinity and potency of traditional active site targeted small molecule inhibitors with the selectivity of inhibitors that target the protein kinase surface outside ATP cleft.

Campbell, S. T., Carlson, K. J., Buchholz, C. J., Helmers, M. R., & Ghosh, I. (2015). Mapping the BH3 Binding Interface of Bcl-X-L, Bcl-2, and Mcl-1 Using Split-Luciferase Reassembly. BIOCHEMISTRY, 54(16), 2632-2643.
Yao, S., Ghosh, I., Zutshi, R., & Chmielewski, J. (1997). A pH-modulated, self-replicating peptide. Journal of the American Chemical Society, 119(43), 10559-10560.
Ghosh, I., Issac, R., & Chmielewski, J. (1999). Structure-function relationship in a β-sheet peptide Inhibitor of E47 dimerization and DNA binding. Bioorganic and Medicinal Chemistry, 7(1), 61-66.

PMID: 10199656;Abstract:

A β-sheet peptide inhibitor, 2H10, has been developed that inhibits the dimerization of the transcription factor E47. Inhibition of E47 dimerization has been demonstrated to also inhibit the DNA binding of this transcription factor. Truncated peptides based on 2H10 have demonstrated that the β-sheet content of these peptides directly correlates with their inhibitory properties. Individual residues within 2H10 were identified that were responsible for the β-sheet secondary structure by employing an alanine replacement strategy. The β-sheet character of the alanine mutants also correlated well with their inhibition of E47 DNA binding. These results provide further evidence that interactions between the interfacial peptide inhibitors of E47 and the transcription factor itself are mediated by a β-sheet structure. Copyright (C) 1999 Elsevier Science Ltd.