Proteins encoded by human genome are involved in about 650000 binary interactions. These protein-protein interactions control practically all biological processes. Ability to manipulate these interactions is crucial for finding cures for the vast majority of human diseases. Conventional high-throughput screens for small molecule blockers of protein-protein interactions produce a disappointingly small number of lead compounds. In addition, screening procedures and subsequent structure optimization are laborious, lengthy and expensive. Meanwhile, specific folds inherent at the interfaces of the interacting proteins have been successfully mimicked for inhibition of the target interactions. Protein fragments involved in interaction can be used for inhibition of these interactions. However, peptides corresponding to fragments of protein primary structures tend to have little or no defined conformation, which results in low efficacy and poor stability in circulation. Consequently, the major effort in mimicking the interface is directed towards making the mimicking peptide or peptidomimetic as rigid as feasible. Strategies have been developed that allow simulation of reverse turns, beta-sheets and alpha-helixes. Cyclization is the most frequently used approach to affect stabilization of both beta-turns and alpha-helices. However, for inhibitors of intracellular protein-protein contacts, there remains the problem of cell permeability. Hydrocarbon-stapled alpha-helix peptidomimetics have demonstrated improved cell penetration, but this method is applicable only to helical fragments of proteins. We have recently found that membrane tethering stabilizes the structure of a peptide and converts it into a potent cell-permeable inhibitor of the corresponding protein. The approach allows for straightforward generation of potent and selective inhibitors of the target proteins. Utilizing the approach, we have developed selective inhibitors of STAT1, STAT3, STAT5 transcription factors, Hedgehog pathway, insulin-like growth factor 1 receptor, Jak1 and Jak2 kinases, interleukin 10 and interferon gamma signaling. Lipopeptides represent a new type of potential therapeutics with a wide range of applications.
| Lu, Xiuxiu; Nowicka, Urszula; Sridharan, Vinidhra et al. (2017) Structure of the Rpn13-Rpn2 complex provides insights for Rpn13 and Uch37 as anticancer targets. Nat Commun 8:15540 |
| Zdanov, Stephanie; Mandapathil, Magis; Abu Eid, Rasha et al. (2016) Mutant KRAS Conversion of Conventional T Cells into Regulatory T Cells. Cancer Immunol Res 4:354-65 |
| Nim, Satra; Jeon, Jouhyun; Corbi-Verge, Carles et al. (2016) Pooled screening for antiproliferative inhibitors of protein-protein interactions. Nat Chem Biol 12:275-81 |
| Muratcioglu, Serena; Chavan, Tanmay S; Freed, Benjamin C et al. (2015) GTP-Dependent K-Ras Dimerization. Structure 23:1325-35 |
| Chavan, Tanmay S; Jang, Hyunbum; Khavrutskii, Lyuba et al. (2015) High-Affinity Interaction of the K-Ras4B Hypervariable Region with the Ras Active Site. Biophys J 109:2602-2613 |
| Jang, Hyunbum; Abraham, Sherwin J; Chavan, Tanmay S et al. (2015) Mechanisms of membrane binding of small GTPase K-Ras4B farnesylated hypervariable region. J Biol Chem 290:9465-77 |
| Kosakowska-Cholody, T; Lin, J; Srideshikan, S M et al. (2014) HKH40A downregulates GRP78/BiP expression in cancer cells. Cell Death Dis 5:e1240 |
| Plisov, Sergey; Wang, Honghe; Tarasova, Nadya et al. (2014) Protein/peptide transduction in metanephric explant culture. Methods Mol Biol 1092:255-67 |
| Zhao, Yunjie; Zeng, Chen; Tarasova, Nadya I et al. (2013) A new role for STAT3 as a regulator of chromatin topology. Transcription 4:227-31 |
| Timofeeva, Olga A; Tarasova, Nadya I; Zhang, Xueping et al. (2013) STAT3 suppresses transcription of proapoptotic genes in cancer cells with the involvement of its N-terminal domain. Proc Natl Acad Sci U S A 110:1267-72 |
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