Research Information
Research Interests
Our research interest is in the development of ultra-stable insulin analogs. Insulin's instability lies in its enhanced susceptibility to chemical degradation and formation of insoluble fibrils (fibrillation). We hypothesize that flexible elements in the secondary structure participate in protein-protein interaction leading to fibrillation. The goal is to dampen flexibility by “stapling” the A-and B-chains of the insulin molecule with peptide tethers of varying lengths to generate single-chain analogs that are ultra-stable, exhibit low mitogenicity and are biologically potent. Another approach is the use of halogenated substitutions like fluorine, in key residues. Fluorous substitutions have been used in drugs such as LipitorTM and ProzacTM to enhance their bioactivities. A long term goal is in its application in programmable implantable insulin pumps to enable peritoneal delivery of insulin in the treatment of Type I Diabetes Mellitus.
Another research interest is directed towards understanding the contribution of kinetic control in transcriptional activation. Protein-directed DNA bending is proposed to regulate assembly of higher-order DNA-multiprotein complexes (“enhanceosomes” and “repressosomes”). SRY, the human male-determining factor encoded by the Y chromosome, is used as a model to decipher the structural mechanisms by which the bent SRY-DNA complex achieves kinetic stability, the relationship to transcriptional activation, and in turn developmental phenotype. Clinical mutations are utilized as probes of general structure-function relationships to evaluate kinetic control of transcriptional regulation.
Publications
- Rege N.K., Wickramasinghe N.P., Tustan A.N., Phillips N.F.B., Yee V.C., Ismail-Beigi F., Weiss M.A.
“Structure-based stabilization of insulin as a therapeutic protein assembly via enhanced aromatic-aromatic interactions.”
J Biol Chem. 293(28):10895-10910 (2018). - Glidden M.D., Aldabbagh K., Phillips N.B., Carr K., Chen Y.S., Whittaker J., Phillips M., Wickramasinghe N.P., Rege N., Swain M., Peng Y., Yang Y., Lawrence M.C., Yee V.C., Ismail-Beigi F., Weiss M.A.
“An ultra-stable single-chain insulin analog resists thermal inactivation and exhibits biological signaling duration equivalent to the native protein.”
J Biol Chem. 293(1):47-68 (2018). - Glidden M.D., Yang Y., Smith N.A., Phillips N.B., Carr K., Wickramasinghe N.P., Ismail-Beigi F., Lawrence M.C., Smith B.J., Weiss M.A.
“Solution structure of an ultra-stable single-chain insulin analog connects protein dynamics to a novel mechanism of receptor binding.”
J Biol Chem. 293(1):69-88 (2018). - Rege N.K., Phillips N.F.B., Weiss M.A.
“Development of glucose-responsive 'smart' insulin systems.”
Curr Opin Endocrinol Diabetes Obes. 24(4):267-278 (2017). - El Hage K., Pandyarajan V., Phillips N.B., Smith B.J., Menting J.G., Whittaker J., Lawrence M.C., Meuwly M., Weiss M.A.
“Extending Halogen-based Medicinal Chemistry to Proteins: IODO-INSULIN AS A CASE STUDY.”
J Biol Chem 291(53):27023-27041 (2016). - Racca J.D., Chen Y.S., Yang Y., Phillips N.B., Weiss M.A.
“Human Sex Determination at the Edge of Ambiguity: INHERITED XY SEX REVERSAL DUE TO ENHANCED UBIQUITINATION AND PROTEASOMAL DEGRADATION OF A MASTER TRANSCRIPTION FACTOR. ”
J Biol Chem 291(42):22173-22195. (2016). - Pandyarajan V., Phillips N.B., Rege N., Lawrence M.C., Whittaker J., Weiss M.A.
“Contribution of TyrB26 to the Function and Stability of Insulin: STRUCTURE-ACTIVITY RELATIONSHIPS AT A CONSERVED HORMONE-RECEPTOR INTERFACE. ”
J Biol Chem 291(25):12978-90 (2016). - Liu M., Haataja L., Wright J., Wickramasinghe N. P., Hua Q. X., Phillips N. F., Barbetti F., Weiss M. A., and Arvan P.
“Mutant INS-gene induced diabetes of youth: proinsulin cysteine residues impose dominant-negative inhibition on wild-type proinsulin transport”
PLoS One 5 (10): e13333 (2010). - Phillips N. B., Wan Z. L., Whittaker L., Hu S. Q., Huang K., Hua Q. X., Whittaker J., Ismail-Beigi F., and Weiss M. A.
“Supramolecular protein engineering: design of zinc-stapled insulin hexamers as a long acting depot”
J Biol Chem 285 (16): 11755-9 (2010). - Sohma Y., Hua Q. X., Liu M., Phillips N. B., Hu S. Q., Whittaker J., Whittaker L. J., Ng A., Roberts C. T., Jr., Arvan P., Kent S. B., and Weiss M. A.
“Contribution of residue B5 to the folding and function of insulin and IGF-I: constraints and fine-tuning in the evolution of a protein family”
J Biol Chem 285 (7): 5040-55 (2010). - Yang Y., Petkova A., Huang K., Xu B., Hua Q. X., Ye I. J., Chu Y. C., Hu S. Q., Phillips N. B., Whittaker J., Ismail-Beigi F., Mackin R. B., Katsoyannis P. G., Tycko R., and Weiss M. A.
“An Achilles' heel in an amyloidogenic protein and its repair: insulin fibrillation and therapeutic design”
J Biol Chem 285 (14): 10806-21 (2010). - Zhao M., Wan Z. L., Whittaker L., Xu B., Phillips N. B., Katsoyannis P. G., Ismail-Beigi F., Whittaker J., and Weiss M. A.
“Design of an insulin analog with enhanced receptor binding selectivity: rationale, structure, and therapeutic implications”
J Biol Chem 284 (46): 32178-87 (2009). - Li B., Phillips N. B., Jancso-Radek A., Ittah V., Singh R., Jones D. N., Haas E., and Weiss M. A.
“SRY-directed DNA bending and human sex reversal: reassessment of a clinical mutation uncovers a global coupling between the HMG box and its tail”
J Mol Biol 360 (2): 310-28 (2006). - Phillips N. B., Jancso-Radek A., Ittah V., Singh R., Chan G., Haas E., and Weiss M. A.
“SRY and human sex determination: the basic tail of the HMG box functions as a kinetic clamp to augment DNA bending”
J Mol Biol 358 (1): 172-92 (2006).