Epigenetics
Epigenetics research delves into the molecular mechanisms that control gene expression and cellular traits without altering the underlying DNA sequence. One crucial aspect of this field is the role of small molecules, which act as powerful regulators of epigenetic modifications. These small compounds, typically comprising a few dozen to a few hundred atoms, have emerged as essential tools in understanding and manipulating the epigenome.
- DNA Methylation Inhibitors: Small molecules like 5-azacytidine and 5-aza-2'-deoxycytidine are DNA methyltransferase inhibitors. They block the addition of methyl groups to DNA, leading to DNA demethylation. This can reactivate silenced genes, potentially offering therapeutic avenues for conditions like cancer.
- HDAC inhibitors: HDACs remove acetyl groups from histone proteins, contributing to gene repression. Small molecule HDAC inhibitors, such as Vorinostat and Romidepsin, can reverse this process by increasing histone acetylation, allowing genes to be more accessible for transcription. These inhibitors are being explored for cancer therapy and other conditions.
- Histone Methyltransferase Inhibitors: Small molecules like GSK126 inhibit specific histone methyltransferases, affecting histone methylation patterns. This can alter gene expression, making them promising candidates for cancer and other diseases with epigenetic dysregulation.
- RNA Modulators: Small molecules can also target non-coding RNAs involved in epigenetic regulation. For instance, small molecules called small interfering RNAs (siRNAs) can be designed to target and degrade specific long non-coding RNAs, influencing gene expression.
- Epigenetic Reader Domain Inhibitors: These small molecules target proteins that recognize and bind to specific epigenetic marks. Examples include inhibitors of bromodomain-containing proteins (BET inhibitors), which can disrupt gene regulation by interfering with protein-DNA interactions.
Small molecules in epigenetics research not only provide insights into the fundamental biology of gene regulation but also hold immense promise for developing novel therapeutics. Their ability to selectively modulate specific epigenetic marks and pathways has led to ongoing clinical trials and drug development efforts for various diseases, including cancer, neurological disorders, and inflammatory conditions. Understanding and harnessing the power of these small molecules is at the forefront of modern epigenetics research, offering new hope for precision medicine and targeted therapies.
3 key components involved in the regulation of epigenetic modifications
Epigenetics Writer
Epigenetics writers are enzymes responsible for adding chemical marks or modifications to DNA or histone proteins. These marks include DNA methylation (addition of methyl groups to DNA) and histone modifications (such as acetylation, methylation, phosphorylation, etc.).
Epigenetics Reader
Function: Epigenetics readers are proteins that can recognize and bind to specific epigenetic marks on DNA or histones. These reader proteins interpret the epigenetic code and facilitate downstream cellular processes, such as gene activation or repression.
Epigenetics Eraser
Function: Epigenetics erasers are enzymes responsible for removing or reversing epigenetic marks on DNA or histones. This process allows for the dynamic regulation of gene expression and the resetting of epigenetic states during various stages of development and in response to environmental changes.
-
HCV NS3/4A protease inhibitor
Danoprevir is a potent inhibitor of the HCV NS3/4A serine protease.- Mahim Khan, .et al. , BMC Complement Med Ther, 2022, Apr 2;22(1):98 PMID: 35366855
- Inês GARCEZ PALHA, .et al. , Biol Open, 2018, Nov 7 PMID: 30404898
- Hui Shen, .et al. , PLoS One., 2013, 8(12): e82299 PMID: 24358168
-
serine protease inhibitor
Nafamostat is an anticoagulant. Broad spectrum serine protease inhibitor. Reduces eosinophil infiltration, mast cell activation and airway responsiveness in a murine model of asthma. -
HMG-CoA reductase inhibitor
Pitavastatin Calcium is a competitive inhibitor of the enzyme HMGCR (HMG-CoA reductase) results in a reduction in LDL cholesterol synthesis.- Weizhen Chen, .et al. , Biomaterials, 2021, 280:121260 PMID: 34823885
- Karis Tutuska, .et al. , Cell Death Dis, 2020, Apr; 11(4): 274 PMID: 32332697
- D Jarmuzek, .et al. , J Photochem Photobiol A Chem, 2019, November
- Marwan Ibrahim Abdullah, .et al. , Sci Rep, 2017, 7: 8090 PMID: 28808351
-
HIV Protease inhibitor
Ritonavir is a protease inhibitor with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Protease inhibitors block the part of HIV called protease.Ritonavir inhibits the HIV viral proteinase enzyme which prevents cleavage of the gag-pol polyprotein, resulting in noninfectious, immature viral particles. -
HMG-CoA reductase inhibitor
Rosuvastatin (Crestor) is a member of the drug class of statins, used to treat high cholesterol and related conditions, and to prevent cardiovascular disease. Rosuvastatin is a competitive inhibitor of the enzyme HMG-CoA reductase, having a mechanism of action similar to that of other statins. -
HCV NS3-4A protease inhibitor
Telaprevir (VX-950) is known as protease inhibitors that inhibits the hepatitis C virus NS3.4A serine protease.- Mahim Khan, .et al. , BMC Complement Med Ther, 2022, Apr 2;22(1):98 PMID: 35366855
- Adita Ayu Permanasari, .et al. , BMC Complement Med Ther, 2021, Oct 12;21(1):260 PMID: 34641875
- Che C Colpitts, .et al. , eLife, 2020, 9: e52237 PMID: 32539931
- TS Wahyuni, .et al. , Southeast Asian J Trop Med public health, 2020, 51(1)
- Stefan Bittmann, .et al. , J Regen Biol Med, 2020, 2(2):1-3
- Wahyuni TS, .et al. , J Basic Clin Physiol Pharmacol, 2019, Dec 14 PMID: 31837259
- Jacobs CL, .et al. , Nat Methods, 2018, Jul;15(7):523-526 PMID: 29967496
- Apriyanto DR, .et al. , Jpn J Infect Dis, 2016, May 20;69(3):213-20 PMID: 26255732
- Mizuki Yamamoto, .et al. , Antimicrob Agents Chemother, 2016, Nov; 60(11): 6532-6539 PMID: 27550352
-
HIV reverse transcriptase inhibitor
Tenofovir is in a class of medications called nucleoside reverse transcriptase inhibitors (NRTIs). It works by decreasing the amount of HIV in the blood. -
nucleotide reverse transcriptase inhibitor
Tenofovir Disoproxil Fumarate is employed as an anti-HIV agend and a reverse transcriptase inhibitor.- Kazumoto Murata, .et al. , Gut, 2018, Feb; 67(2): 362-371 PMID: 27789659
-
HMG-CoA reductase inhibitor
Rosuvastatin is a member of the drug class of statins, used to treat high cholesterol and related conditions, and to prevent cardiovascular disease. -
Proteasome inhibitor
PR-171 (Carfilzomib) is a tetrapeptide epoxyketone and a selective proteasome inhibitor. It is an analog of epoxomicin.- Andrew Thorne, .et al. , PLoS One, 2023, Jun 8;18(6):e0286783 PMID: 37289679
- Mahmood Barani, .et al. , J Drug Deliv Sci Technol, 2023, 81: 104268
- Ori Kalid, .et al. , Chem Biol Drug Des, 2022, Mar 24 PMID: 35322538
- Abbas Rahdar, .et al. , Journal of Molecular Liquids, 2022, 346: 118271
- Sadegh Zarei, .et al. , J Appl Biotechnol Rep, 2019, June;6(2):45-49
- Fujita KI, .et al. , J Pharm Sci, 2017, Sep;106(9):2632-2641 PMID: 28479358
-
HCV Protease Inhibitor
Boceprevir is a protease inhibitor used as a treatment for hepatitis C genotype 1.- Ueda Y, .et al. , Virus Res, 2017, May 2;235:37-48 PMID: 28322919
- Shirasaki T, .et al. , Hepatology., 2014, 60(5):1519-30 PMID: 24962339
-
HIV-1 protease inhibitor
Nelfinavir is a potent and orally bioavailable human immunodeficiency virus HIV-1 protease inhibitor (Ki=2 nM) and is widely prescribed in combination with HIV reverse transcriptase inhibitors for the treatment of HIV infection.- Reiko Watanabe, .et al. , J Med Chem, 2021, Mar 11;64(5):2725-2738 PMID: 33619967
- Yang PM, .et al. , Am J Cancer Res, 2019, Oct 1;9(10):2120-2139 PMID: 31720078
-
viral RNA polymerase inhibitor
T-705, a substituted pyrazine compound, has been found to exhibit potent anti-influenza virus activity in vitro and in vivo.
- Steven B Tillis, .et al. , Microorganisms, 2023, May 24;11(6):1371 PMID: 37374873
- Hyeon-Min Cha, .et al. , ACS Infect Dis, 2023, Apr 14;9(4):1033-1045 PMID: 36912867
- Satoko Yamaoka, .et al. , Antiviral Res, 2022, Apr;200:105291 PMID: 35296419
- Crystal A Mendoza, .et al. , Antiviral Res, 2021, Jan;185:104993 PMID: 33296695
- Liva Checkmahomed, .et al. , Viruses, 2020, Oct; 12(10): 1139 PMID: 33049959
- JE Comer, .et al. , Viruses, 2019, Feb 3;11(2). pii: E137 PMID: 30717492
- Ma J, .et al. , Antiviral Res, 2018, Feb;150:112-122 PMID: 29253498
- Ji-Ae Kim, .et al. , Viruses, 2018, Feb; 10(2): 72 PMID: 29425176
- Haejin Chun, .et al. , Polym Chem, 2018, 9: 2116-2123
- Baz M, .et al. , Viruses, 2018, Nov 3;10(11) PMID: 30400276
- Sehee Park, .et al. , PLoS One., 2014, 9(7): e101325 PMID: 24992479
-
GSK-3 Inhibitor
Tideglusib is a GSK-3 inhibitor currently in phase II clinical trials for the treatment of Alzheimer disease and progressive supranuclear palsy- Vijaya Bharti, .et al. , Cell Rep, 2022, Dec 20;41(12):111826 PMID: 36543138
-
HIV protease inhibitor
Darunavir Ethanolate (Prezista) is an HIV protease inhibitor. -
NS5A inhibitor
Ledipasvir is an inhibitor of the hepatitis C virus HCV NS5A protein- Miyayama Y, .et al. , Microbiol Immunol, 2019, Dec 19 PMID: 31854467
- Sayuri Nitta, .et al. , Scientific Reports, 2019, 9: 5722 PMID: 30952914
- Sayuri Nitta, .et al. , Sci Rep, 2016, 6: 34652 PMID: 27703205
-
HMG-CoA reductase inhibitor
Pitavastatin Lactone is an HMG-CoA reductase inhibitor. -
HIV protease inhibitor
Nelfinavir Mesylate is a potent HIV protease inhibitor with Ki of 2 nM. -
HIV-1 integrase Inhibitor
Bictegravir, also known as GS-9883, is a potent, unboosted, once-Daily HIV-1 Integrase Strand Transfer Inhibitor (INSTI) (IC50 - 1.6 nM) with improved pharmacokinetics and in vitro resistance profile.- Michal S Barski, .et al. , Nat Commun, 2021, Aug 17;12(1):4996 PMID: 34404793
-
HCV NS5A inhibitor
Velpatasvir, also known as GS-5816, is a potent and selective Hepatitis C virus NS5A inhibitor. -
HCV NS5A inhibitor
Ledipasvir acetone is the active pharmaceutical ingredient of Ledipasvir. Ledipasvir is an inhibitor of the hepatitis C virus NS5A, with EC50 values of 34 pM against GT1a and 4 pM against GT1b replicon. -
serine protease inhibitor
Nafamostat is an anticoagulant. Broad spectrum serine protease inhibitor. Reduces eosinophil infiltration, mast cell activation and airway responsiveness in a murine model of asthma. -
serine protease inhibitor
Nafamostat hydrochloride is an anticoagulant. Broad spectrum serine protease inhibitor. Reduces eosinophil infiltration, mast cell activation and airway responsiveness in a murine model of asthma. -
HIV-1 capsid CTD dimerization inhibitor
Ebselen (SPI-1005) is an inhibitor of HIV-1 capsid CTD dimerization. Ebselen can permeate the blood-brain barrier and inhibit inositol monophosphatase (IMPase). Ebselen is a non-toxic seleno-organic drug with anti-inflammatory and antioxidant properties. Ebselen inhibits QSOX1 enzymatic activity and has anticancer activity . -
Plpro inhibitor
PLpro inhibitor is a potent inhibitor of papain-like protease (PLpro) with IC50 of 2.6 uM.