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IMP-1088 is an enzyme inhibitor of the human N-myristoyltransferases NMT1 and NMT2, an analog of Zelenirstat, capable of preventing viruses that require myristoylated proteins for their life cycle such as pox viruses, mammarenaviruses, and rhinoviruses, an area of research relating to potential treatment of the monkeypox, lassa fever, and common cold among others. IMP-1088 works to keep cells from generating infectious virus by targeting the cell instead of the rhinovirus itself. It does this by blocking the NMT protein of the host cell which prevents the virus from assembling its capsid, since viral capsid myristoylation by host NMT is essential for assembly. It is thought unlikely that viruses will evolve resistance to such an approach since IMP-1088 works against the human cell and not the virus. IMP-1088 can inhibit mammarenaviruses such as LCMV virus and the hemorragic fever viruses such as lassa and junin, where IMP-1088 targets the Z matrix protein and the signal peptide of glycoprotein 1 of these viruses, these myristoylated viral proteins are essential for the viral life cycle including assembly, budding and propagation. Both vaccinia and monkeypox viruses have four myristoylated proteins that can be targeted which would interrupt viral lifecycle, inhibition of myristoylation has been shown to completely inhibit viral propagation in combination therapies.
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Brequinar (DuP-785) is a drug that acts as a potent and selective inhibitor of the enzyme dihydroorotate dehydrogenase. It blocks synthesis of pyrimidine based nucleotides in the body and so inhibits cell growth. Brequinar was invented by DuPont Pharmaceuticals in the 1980s. In 2001, Bristol-Myers Squibb acquired DuPont, and in 2017, Clear Creek Bio acquired the rights to brequinar from BMS.
Zelenirstat, also known as PCLX-001, is an investigational new drug that is being evaluated for the treatment of cancer and as an antiviral agent. It is a small molecule inhibitor targets both N-myristoyltransferase 1 (NMT1) and N-myristoyltransferase 2 (NMT2) proteins, which are responsible for myristoylation. Its dual mechanism of action disrupts both cell signaling and energy production in cancer cells.
References
- ↑ "RCSB PDB - 3IWE: Crystal Structure of human type-I N-myristoyltransferase with bound myristoyl-CoA and inhibitor DDD85646". www.rcsb.org. Retrieved January 19, 2025.
- ↑ Witwit, Haydar; Cubitt, Beatrice; Khafaji, Roaa; Castro, Esteban M.; Goicoechea, Miguel; Lorenzo, Maria M.; Blasco, Rafael; Martinez-Sobrido, Luis; de la Torre, Juan C. (January 13, 2025). "Repurposing Drugs for Synergistic Combination Therapies to Counteract Monkeypox Virus Tecovirimat Resistance". Viruses. 17 (1): 92. doi: 10.3390/v17010092 . ISSN 1999-4915.
- ↑ Witwit, Haydar; Betancourt, Carlos Alberto; Cubitt, Beatrice; Khafaji, Roaa; Kowalski, Heinrich; Jackson, Nathaniel; Ye, Chengjin; Martinez-Sobrido, Luis; de la Torre, Juan C. (August 26, 2024). "Cellular N-Myristoyl Transferases Are Required for Mammarenavirus Multiplication". Viruses. 16 (9): 1362. doi: 10.3390/v16091362 . ISSN 1999-4915. PMC 11436053 . PMID 39339839.
- ↑ Gamma, Jay M.; Liu, Qiang; Beauchamp, Erwan; Iyer, Aishwarya; Yap, Megan C.; Zak, Zoulika; Ekstrom, Cassidy; Pain, Rony; Kostiuk, Morris A.; Mackey, John R.; Brandwein, Joseph; Wang, Jean C.Y.; Berthiaume, Luc G. (2025-01-02). "Zelenirstat Inhibits N-Myristoyltransferases to Disrupt Src Family Kinase Signaling and Oxidative Phosphorylation, Killing Acute Myeloid Leukemia Cells". Molecular Cancer Therapeutics. 24 (1): 69–80. doi:10.1158/1535-7163.MCT-24-0307. ISSN 1535-7163. PMC 11694064 . PMID 39382188.
- ↑ Sangha, Randeep; Jamal, Rahima; Spratlin, Jennifer; Kuruvilla, John; Sehn, Laurie H.; Beauchamp, Erwan; Weickert, Michael; Berthiaume, Luc G.; Mackey, John R. (August 2024). "A first-in-human phase I trial of daily oral zelenirstat, a N-myristoyltransferase inhibitor, in patients with advanced solid tumors and relapsed/refractory B-cell lymphomas". Investigational New Drugs. 42 (4): 386–393. doi:10.1007/s10637-024-01448-w. ISSN 0167-6997. PMC 11327210 . PMID 38837078.