What are NMT1 inhibitors and how do they work?

N-Myristoyltransferase 1 (NMT1) inhibitors are emerging as a promising class of therapeutic agents in the field of biomedical research. NMT1 is an enzyme that catalyzes the covalent attachment of myristic acid, a 14-carbon saturated fatty acid, to the N-terminal glycine residue of substrate proteins. This post-translational modification, known as N-myristoylation, is crucial for the proper function, localization, and stability of a variety of proteins involved in numerous cellular processes. By inhibiting NMT1, researchers aim to disrupt these processes, offering potential therapeutic strategies for a range of diseases, including cancer, infectious diseases, and inflammatory disorders.

NMT1 inhibitors work by specifically binding to the active site of the NMT1 enzyme, thereby preventing the attachment of myristic acid to target proteins. This inhibition can lead to the mislocalization and dysfunction of key signaling proteins that rely on myristoylation for their activity. For example, several oncogenic proteins, such as Src family kinases and G-protein subunits, require myristoylation to translocate to cell membranes where they exert their effects. Inhibiting NMT1 can impede these proteins from reaching their proper cellular destinations, thereby blocking the signaling pathways they regulate. Moreover, NMT1 inhibitors can induce proteotoxic stress and apoptosis in cancer cells, making them attractive candidates for anticancer therapy.

The mechanism of NMT1 inhibition involves the competitive or non-competitive binding of small molecules to the enzyme's active site. Competitive inhibitors resemble the natural substrate of the enzyme and compete with it for binding, whereas non-competitive inhibitors bind to a different part of the enzyme, causing conformational changes that reduce its activity. Structural studies of NMT1 and its inhibitors have provided valuable insights into the design of potent and selective inhibitors. For instance, high-throughput screening and rational drug design have led to the discovery of several potent NMT1 inhibitors with high specificity and low off-target effects.

NMT1 inhibitors have shown considerable potential in preclinical studies for various applications. One of the primary areas of interest is cancer therapy. NMT1 is often overexpressed in cancer cells, and its inhibition can selectively target malignant cells while sparing normal tissues. Researchers have demonstrated that NMT1 inhibitors can suppress tumor growth and metastasis in models of breast cancer, leukemia, and other malignancies. Additionally, combining NMT1 inhibitors with other therapeutic agents, such as chemotherapy and targeted therapies, can enhance their efficacy and overcome resistance mechanisms.

Infectious diseases represent another promising application for NMT1 inhibitors. Many pathogens, including viruses, bacteria, and parasites, rely on host-cell N-myristoylation for their replication and survival. For instance, the HIV-1 Gag protein, essential for viral assembly and budding, requires myristoylation for its function. By inhibiting NMT1, researchers aim to disrupt the life cycle of such pathogens and develop novel antiviral and antibacterial therapies. Studies have shown that NMT1 inhibitors can effectively inhibit the replication of viruses like HIV and hepatitis C, as well as protozoan parasites like Trypanosoma brucei, the causative agent of African sleeping sickness.

Inflammatory diseases also present a potential therapeutic target for NMT1 inhibitors. Myristoylation is involved in the regulation of immune cell signaling and the production of pro-inflammatory cytokines. By modulating these pathways, NMT1 inhibitors could offer new treatments for conditions such as rheumatoid arthritis, inflammatory bowel disease, and psoriasis. Preclinical studies have indicated that NMT1 inhibition can reduce inflammation and ameliorate disease symptoms in animal models of these disorders.

In conclusion, NMT1 inhibitors represent a versatile and promising class of therapeutic agents with potential applications across cancer, infectious diseases, and inflammatory conditions. By targeting the fundamental process of N-myristoylation, these inhibitors offer a novel approach to disrupt disease-related signaling pathways. Continued research and development efforts are likely to yield more potent and selective NMT1 inhibitors, paving the way for new and effective treatments in the near future.