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Principal Investigator: Nadya Tarasova
Organization: DIVISION OF BASIC SCIENCES - NCI
Fiscal Year: 2022
Award: $696,075
Funding agency: National Cancer Institute
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 and Ras oncogenes. Inhibitors of STAT1, STAT3 and RAS oncogenes have been tested in mouse models of cancer and have demonstrated remarkable anti-tumor activity. Ras inhibitor is currently in preclinical phase of development. Lipopeptides represent a new type of potential therapeutics with a wide range of applications. Lipopeptide inhibitors are also powerful chemical biology tools. Utilization of selective inhibitors of Ras oncoproteins allowed for uncovering of two previously unknown mechanisms of regulation of the proteins that are responsible for the growth of over 30% of all human tumors. Inhibitors of STAT3 N-terminal domain were instrumental in discovering that this transcription factor is involved in activation of transcription of apoptosis-inhibiting proteins in breast and prostate tumors, but not normal cells. The studies have identified STAT3 N-terminal domain as a promising drug target not only for cancer but infectious diseases like tuberculosis. In addition, we are utilizing in silico screening of specially constructed virtual libraries of compounds for identification of potential inhibitors of protein-protein interactions. The developed technologies allowed for the discoveries of ligands for several non-druggable targets. In addition, virtual screening of super-large libraries containing billions of compounds utilizing novel computational approaches allowed for identification of ligands for several proteins widely considered non-druggable. These include mutant K-ras, STAT3 N-terminal domain, TIGIT (T cell immunoreceptor with Ig and ITIM domains) and several SARS-Cov2 proteins. The studies have shown that expanding synthetically accessible chemical space allows for successful identification of ligands even for very challenging drug targets. In the past couple of years we and other have expanded significantly synthetically accessible part of chemical universe brining total number of compounds to several billion . However, searching these giant databases remains a challenge, largely because every compound can exist in multiple conformations. We have now generated conformer databases for more than 5 billion compounds. Searching of pre-formed conformers significantly accelerates the screens paving the way for a significant increase in searchable chemical space.
Terms: <2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><Affect><Amino Acid Sequence><Apoptosis><Apoptosis Pathway><Basal Transcription Factor><Basal transcription factor genes><Beta Sheet><Biological Function><Biological Process><Biology><Blood Circulation><Bloodstream><Breast Neoplasms><Breast Tumors><C-K-RAS><CCR><COVID-19 S protein><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID19 S protein><COVID19 spike glycoprotein><COVID19 spike protein><CSIF><CSIF-10><Cancer Model><CancerModel><Cancers><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Chemicals><Circulation><Collaborations><Communicable Diseases><Cyclization><Cytokine Synthesis Inhibitory Factor><Data Bases><Databases><Development><Disease><Disorder><Drug Targeting><Drugs><Equipment and supply inventories><Erinaceidae><Gamma interferon><General Transcription Factor Gene><General Transcription Factors><Generalized Growth><Generations><Goals><Growth><Hedgehogs><High Throughput Assay><Human><Hydrocarbons><IFN-Gamma><IFN-g><IFN-γ><IFNG><IFNγ><IGF Type 1 Receptor><IGF-1 Receptor><IGF-I Receptor><IL-10><IL10><IL10A><ITIM><Immune Interferon><Immunoreceptor Tyrosine-Based Inhibitory Motif><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Insulin-Like Growth Factor 1 Receptor><Insulin-Like Growth Factor Type 1 Receptor><Insulin-Like-Growth Factor I Receptor><Interferon Gamma><Interferon Type II><Interferon-gamma><Interleukin 10 Precursor><Interleukin-10><Intracellular Communication and Signaling><Inventory><K-RAS2A><K-RAS2B><K-Ras><K-Ras 2A><K-Ras-2 Oncogene><KRAS><KRAS2><KRAS2 gene><Ki-RAS><Kinases><Knowledge><Lead><Libraries><Ligands><M tuberculosis infection><M. tb infection><M. tuberculosis infection><M.tb infection><M.tuberculosis infection><MGF protein><MGSNF protein><MTB infection><Malignant Neoplasms><Malignant Tumor><Mammary Cancer><Mammary Neoplasms><Medication><Membrane><Methods><Modern Man><Molecular Configuration><Molecular Conformation><Molecular Stereochemistry><Mycobacterium tuberculosis (MTB) infection><Mycobacterium tuberculosis infection><N-terminal><NH2-terminal><Oncogene K-Ras><Oncogene Products><Oncogene Proteins><Oncoproteins><Pathway interactions><Pb element><Penetration><Peptides><Permeability><Pharmaceutic Preparations><Pharmaceutical Preparations><Phase><Phosphotransferase Gene><Phosphotransferases><Primary Protein Structure><Process><Programmed Cell Death><Prostate Neoplasms><Prostate Tumor><Prostatic Neoplasia><Prostatic Neoplasms><Protein Fragment><Proteins><RAS Family Oncogene><RASK2><Ras Inhibitor><Regulation><Research><Retrovirus Associated Sequence Oncogene><SARS-CoV-2 S protein><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV2 S protein><SARS-CoV2 spike glycoprotein><SARS-CoV2 spike protein><STAT1><STAT1 gene><STAT3><STAT3 gene><STAT5><STAT5A><STAT5A gene><STAT5a Transcription Factor><STAT91><Screening procedure><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Signal Transducer and Activator of Transcription 5A><Signal Transduction><Signal Transduction Systems><Signaling><Speed><Stat5 protein><Stat5a protein><Stat5alpha protein><Structure><T-Cells><T-Lymphocyte><TB infection><Technology><Testing><Therapeutic><Tissue Growth><Transcription Activation><Transcription Factor Proto-Oncogene><Transcription factor genes><Transcriptional Activation><Transphosphorylases><Tuberculosis><alpha helix><beta pleated sheet><biological signal transduction><conformation><conformational state><conformer><coronavirus disease 2019 S protein><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><data base><developmental><disseminated TB><disseminated tuberculosis><drug discovery><drug/agent><heavy metal Pb><heavy metal lead><high throughput screening><human disease><improved><in silico><infection due to Mycobacterium tuberculosis><inhibitor><lFN-Gamma><malignancy><mammary gland factor><mammary gland-specific nuclear factor><mammary tumor><membrane structure><mouse model><murine model><mutant><neoplasm/cancer><new approaches><novel><novel approaches><novel strategies><novel strategy><ontogeny><pathway><peptide mimetic><peptide mimic><peptidomimetics><pre-clinical><preclinical><protein protein interaction><protein sequence><ras Oncogene><screening><screening tools><signal tranducer and activator of transcription 5><simulation><small molecule><thymus derived lymphocyte><tool><transcription factor><tuberculosis infection><tuberculous spondyloarthropathy><tumor><v-Ki-RAS2 Kirsten Rat Sarcoma 2 Viral Oncogene Homolog><virtual><virtual library><virtual screening><virtual screenings><α-helix><β-Sheet><β-pleated sheet>