Halicin

Last updated
Halicin
Halicin.svg
Clinical data
Trade names Halicin
Legal status
Legal status
Identifiers
  • 5-[(5-Nitro-1,3-thiazol-2-yl)sulfanyl]-1,3,4-thiadiazol-2-amine
CAS Number
PubChem CID
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C5H3N5O2S3
Molar mass 261.29 g·mol−1
3D model (JSmol)
  • C1=C(SC(=N1)SC2=NN=C(S2)N)[N+](=O)[O-]
  • InChI=1S/C5H3N5O2S3/c6-3-8-9-5(14-3)15-4-7-1-2(13-4)10(11)12/h1H,(H2,6,8)
  • Key:NQQBNZBOOHHVQP-UHFFFAOYSA-N

Halicin (SU-3327) is an experimental drug that acts as an enzyme inhibitor of c-Jun N-terminal kinase (JNK). [1] [2] [3] Originally, it was researched for the treatment of diabetes, [4] but development was discontinued for this application due to poor results in testing.[ citation needed ] In 2019, this molecule was found by an artificial intelligence (AI) model to show antibiotic properties against a number of bacteria. [5]

Contents

History

Halicin was previously known as SU-3327, [6] developed by a group of researchers from Burnham Institute for Medical Research, United States in 2009 for investigations into diabetes treatment. [4] Researchers named the molecule after the fictional artificial intelligence system Hal from 2001: A Space Odyssey. [5]

Antibiotic properties

Halicin was identified by artificial intelligence researchers, including bioengineer James Collins, at the MIT Jameel Clinic in 2019 using an in silico deep learning approach, as a likely broad-spectrum antibiotic. [5] [7] The process took just three days. [8] This likelihood was verified by in vitro cell culture testing, followed by in vivo tests in mice. [9] It showed activity against drug-resistant strains of Clostridiodes difficile , Acinetobacter baumannii , and Mycobacterium tuberculosis , with an unusual mechanism of action involving the sequestration of iron inside the bacterial cells, that thereby interferes with their ability to regulate the pH balance across the cell membrane properly. Since this is a different mode of action from most antibiotics, halicin retained activity against bacterial strains resistant to many commonly used drugs. [10]

Preliminary studies suggest that halicin kills bacteria by disrupting their ability to maintain an electrochemical gradient across their cell membranes. This gradient is necessary, among other functions, to produce adenosine triphosphate (ATP, molecules that cells use to store and transfer energy), so if the gradient breaks down, the cells die. This type of killing mechanism could be difficult for bacteria to develop resistance to. [7]

Related Research Articles

An electron transport chain (ETC) is a series of protein complexes and other molecules that transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples this electron transfer with the transfer of protons (H+ ions) across a membrane. Many of the enzymes in the electron transport chain are embedded within the membrane.

<span class="mw-page-title-main">Nicotinamide adenine dinucleotide</span> Chemical compound which is reduced and oxidized

Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine nucleobase and the other, nicotinamide. NAD exists in two forms: an oxidized and reduced form, abbreviated as NAD+ and NADH (H for hydrogen), respectively.

<span class="mw-page-title-main">Protein disulfide-isomerase</span> Class of enzymes

Protein disulfide isomerase, or PDI, is an enzyme in the endoplasmic reticulum (ER) in eukaryotes and the periplasm of bacteria that catalyzes the formation and breakage of disulfide bonds between cysteine residues within proteins as they fold. This allows proteins to quickly find the correct arrangement of disulfide bonds in their fully folded state, and therefore the enzyme acts to catalyze protein folding.

Glutathione <i>S</i>-transferase Family of enzymes

Glutathione S-transferases (GSTs), previously known as ligandins, are a family of eukaryotic and prokaryotic phase II metabolic isozymes best known for their ability to catalyze the conjugation of the reduced form of glutathione (GSH) to xenobiotic substrates for the purpose of detoxification. The GST family consists of three superfamilies: the cytosolic, mitochondrial, and microsomal—also known as MAPEG—proteins. Members of the GST superfamily are extremely diverse in amino acid sequence, and a large fraction of the sequences deposited in public databases are of unknown function. The Enzyme Function Initiative (EFI) is using GSTs as a model superfamily to identify new GST functions.

c-Jun N-terminal kinases Chemical compounds

c-Jun N-terminal kinases (JNKs), were originally identified as kinases that bind and phosphorylate c-Jun on Ser-63 and Ser-73 within its transcriptional activation domain. They belong to the mitogen-activated protein kinase family, and are responsive to stress stimuli, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock. They also play a role in T cell differentiation and the cellular apoptosis pathway. Activation occurs through a dual phosphorylation of threonine (Thr) and tyrosine (Tyr) residues within a Thr-Pro-Tyr motif located in kinase subdomain VIII. Activation is carried out by two MAP kinase kinases, MKK4 and MKK7, and JNK can be inactivated by Ser/Thr and Tyr protein phosphatases. It has been suggested that this signaling pathway contributes to inflammatory responses in mammals and insects.

<span class="mw-page-title-main">Mitogen-activated protein kinase 9</span> Protein-coding gene in the species Homo sapiens

Mitogen-activated protein kinase 9 is an enzyme that in humans is encoded by the MAPK9 gene.

The unfolded protein response (UPR) is a cellular stress response related to the endoplasmic reticulum (ER) stress. It has been found to be conserved between mammalian species, as well as yeast and worm organisms.

<span class="mw-page-title-main">Transcription factor Jun</span> Mammalian protein found in Homo sapiens

Transcription factor Jun is a protein that in humans is encoded by the JUN gene. c-Jun, in combination with protein c-Fos, forms the AP-1 early response transcription factor. It was first identified as the Fos-binding protein p39 and only later rediscovered as the product of the JUN gene. c-jun was the first oncogenic transcription factor discovered. The proto-oncogene c-Jun is the cellular homolog of the viral oncoprotein v-jun. The viral homolog v-jun was discovered in avian sarcoma virus 17 and was named for ju-nana, the Japanese word for 17. The human JUN encodes a protein that is highly similar to the viral protein, which interacts directly with specific target DNA sequences to regulate gene expression. This gene is intronless and is mapped to 1p32-p31, a chromosomal region involved in both translocations and deletions in human malignancies.

<span class="mw-page-title-main">MAPK8</span> Protein-coding gene in the species Homo sapiens

Mitogen-activated protein kinase 8 is a ubiquitous enzyme that in humans is encoded by the MAPK8 gene.

<span class="mw-page-title-main">MAP2K4</span> Protein-coding gene in the species Homo sapiens

Dual-specificity mitogen-activated protein kinase kinase 4 is an enzyme that in humans is encoded by the MAP2K4 gene.

<span class="mw-page-title-main">MAPK8IP1</span> Protein-coding gene in the species Homo sapiens

C-jun-amino-terminal kinase-interacting protein 1 is an enzyme that in humans is encoded by the MAPK8IP1 gene.

<span class="mw-page-title-main">Two-component regulatory system</span>

In the field of molecular biology, a two-component regulatory system serves as a basic stimulus-response coupling mechanism to allow organisms to sense and respond to changes in many different environmental conditions. Two-component systems typically consist of a membrane-bound histidine kinase that senses a specific environmental stimulus and a corresponding response regulator that mediates the cellular response, mostly through differential expression of target genes. Although two-component signaling systems are found in all domains of life, they are most common by far in bacteria, particularly in Gram-negative and cyanobacteria; both histidine kinases and response regulators are among the largest gene families in bacteria. They are much less common in archaea and eukaryotes; although they do appear in yeasts, filamentous fungi, and slime molds, and are common in plants, two-component systems have been described as "conspicuously absent" from animals.

<span class="mw-page-title-main">MAP3K1</span> Protein-coding gene in the species Homo sapiens

Mitogen-activated protein kinase kinase kinase 1 (MAP3K1) is a signal transduction enzyme that in humans is encoded by the autosomal MAP3K1 gene.

<span class="mw-page-title-main">MAP2K7</span> Protein-coding gene in the species Homo sapiens

Dual specificity mitogen-activated protein kinase kinase 7, also known as MAP kinase kinase 7 or MKK7, is an enzyme that in humans is encoded by the MAP2K7 gene. This protein is a member of the mitogen-activated protein kinase kinase family. The MKK7 protein exists as six different isoforms with three possible N-termini and two possible C-termini.

<span class="mw-page-title-main">MAP3K4</span> Protein-coding gene in the species Homo sapiens

Mitogen-activated protein kinase kinase kinase 4 is an enzyme that in humans is encoded by the MAP3K4 gene.

<span class="mw-page-title-main">SH3BP5</span> Protein-coding gene in the species Homo sapiens

SH3 domain-binding protein 5 is a protein that in humans is encoded by the SH3BP5 gene.

<span class="mw-page-title-main">MAPK10</span> Protein-coding gene in the species Homo sapiens

Mitogen-activated protein kinase 10 also known as c-Jun N-terminal kinase 3 (JNK3) is an enzyme that in humans is encoded by the MAPK10 gene.

mTORC1 Protein complex

mTORC1, also known as mammalian target of rapamycin complex 1 or mechanistic target of rapamycin complex 1, is a protein complex that functions as a nutrient/energy/redox sensor and controls protein synthesis.

<span class="mw-page-title-main">Cytotrienin A</span> Chemical compound

Cytotrienin A is a secondary metabolite isolated from Streptomyces sp. RK95-74 isolated from soil in Japan in 1997. Cyt A is an ansamycin. Cytotrienin A induces apoptosis on HL-60 cells, as well as inhibiting translation in eukaryotes by inhibiting eukaryotic elongation factor 1A (eEF1A), which can act as an oncogene. These functions lead to the potential of the microbial metabolite acting as an anticancer agent, specifically for blood cancers, as it has proved to be more effective with leukemic cell lines. Cyt A is thought to induce apoptosis by activating c-Jun N-terminal Kinase (JNK), p38 mitogen-activated protein kinase (MAPK), and p36 myelin basic protein (MBP) kinase.

Regina Barzilay is an Israeli-American computer scientist. She is a professor at the Massachusetts Institute of Technology and a faculty lead for artificial intelligence at the MIT Jameel Clinic. Her research interests are in natural language processing and applications of deep learning to chemistry and oncology.

References

  1. ↑ Augustine C, Cepinskas G, Fraser DD (August 2014). "Traumatic injury elicits JNK-mediated human astrocyte retraction in vitro". Neuroscience. 274: 1–10. doi:10.1016/j.neuroscience.2014.05.009. PMID   24838066. S2CID   9498486.
  2. ↑ Jang S, Javadov S (2014). "Inhibition of JNK aggravates the recovery of rat hearts after global ischemia: the role of mitochondrial JNK". PLOS ONE. 9 (11): e113526. Bibcode:2014PLoSO...9k3526J. doi: 10.1371/journal.pone.0113526 . PMC   4244102 . PMID   25423094.
  3. ↑ Jang S, Yu LR, Abdelmegeed MA, Gao Y, Banerjee A, Song BJ (December 2015). "Critical role of c-jun N-terminal protein kinase in promoting mitochondrial dysfunction and acute liver injury". Redox Biology. 6: 552–564. doi:10.1016/j.redox.2015.09.040. PMC   4625008 . PMID   26491845.
  4. 1 2 De SK, Stebbins JL, Chen LH, Riel-Mehan M, Machleidt T, Dahl R, et al. (April 2009). "Design, synthesis, and structure-activity relationship of substrate competitive, selective, and in vivo active triazole and thiadiazole inhibitors of the c-Jun N-terminal kinase". Journal of Medicinal Chemistry. 52 (7): 1943–52. doi:10.1021/jm801503n. PMC   2667321 . PMID   19271755.
  5. 1 2 3 "Artificial Intelligence Yields New Antibiotic". The MIT Campaign for a Better World. Retrieved 2020-11-13.
  6. ↑ "AI finds molecules that kill bacteria, but would they make good antibiotics?". Chemical and engineering news (C&EN). 26 February 2020. Archived from the original on 29 February 2020. Retrieved 22 March 2023.
  7. 1 2 Trafton A (February 20, 2020). "Artificial intelligence yields new antibiotic". MIT News Office.
  8. ↑ May, Mike (2023). "How to fight antibiotic resistance". Nature Medicine. 29 (7): 1583–1586. doi:10.1038/d41591-023-00043-5. ISSN   1078-8956.
  9. ↑ Sample I (February 20, 2020). "Powerful antibiotic discovered using machine learning for first time". The Guardian.
  10. ↑ Stokes JM, Yang K, Swanson K, Jin W, Cubillos-Ruiz A, Donghia NM, et al. (February 2020). "A Deep Learning Approach to Antibiotic Discovery". Cell. 180 (4): 688–702.e13. doi: 10.1016/j.cell.2020.01.021 . PMC   8349178 . PMID   32084340.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.