Quantitative Chemical Biology

Toxic structured RNAs cause many different diseases.  For example, myotonic dystrophy type 1 (DM1) is caused by r(CUG) repeat expansion [r(CUG) exp ] harboured in the 3’ untranslated region (UTR) of the dystrophia myotonica protein kinase (DMPK) mRNA. DM1 is one of the most common forms of adult-onset muscular dystrophy, affecting approximately 1 in 8,000 people.  r(CUG) exp  binds to and sequesters various proteins, particularly the pre-mRNA splicing regulator muscleblind-like 1 (MBNL1), which limits the number of MBNL1 available to regulate pre-mRNA splicing and causes system-wide defects. Recently, r(CUG) exp  was confirmed to cause another disease called Fuchs endothelial corneal dystrophy (FECD), in which the repeat expansion resides in intron 3 of the transcription factor 4 (TCF4) pre-mRNA. FECD is a dominantly inherited corneal disease that affects as many as 5% of Caucasian males and results in vision impairment. Similar to DM1, r(CUG) exp  al...

Cancer cells exploit proteins involved in energy metabolism to maintain a steady supply of building blocks necessary for increased proliferation. Many transporters play a role in the process of shuttling water, nutrients, ions, and various metabolic products across the cell membrane, including the solute carrier (SLC) group of proteins. The SLC protein group consists of more than 400 proteins organized into more than 50 families. For example, the SLC9 family is involved in intracellular pH homeostasis, with increased SL9 activity resulting in an elevated intracellular pH and cytosolic alkalinization in cancer. Currently there 12 FDA approved drugs targeting SLC proteins for conditions ranging from hypertension to depression, but recent studies suggest SLC proteins may be attractive targets for cancer drug development. With this end goal, Bensimon et al., aimed to investigate if multi-pass transmembrane proteins like SLCs can be chemically degraded. To first explore this aim, th...

Evading apoptosis is one of hallmarks of cancer and highly associated with chemotherapy resistance. The BCL-2 family of proteins govern both intrinsic apoptosis and are frequently dysregulated in various cancers. So far, small molecules have been developed to effectively block BCL-2, BCL-XL, and MCL-1. A selective BCL-2 inhibitor, Venetoclax, is the first FDA approved for the treatment of CLL, and other BCL-XL and MCL-1 inhibitors are currently in clinical trials. Among six anti-apoptotic BCL-2 family proteins, BFL-1 is considered undruggable, being the least studied, however, a growing body of evidence suggests its value as a therapeutic target acting as resistant factors to other BCL-2 family proteins inhibitors in lymphoma and to MAPK inhibitors in melanoma. Thus, selective BFL-1 inhibitors held clinical promise. Recently, a small molecular covalent BFL-1 inhibitor targeting cysteine has been described in a paper in “Cell Chemical Biology”. The unique cysteine55 in the BH3...

Tuberculosis (TB) remains a major cause of death globally, primarily in underdeveloped countries, and imposes approximately 12 billion USD annually in economic burdens to society. Furthermore, multi-drug-resistant (MDR) and extreme-drug-resistant (XTR) TB are widespread illnesses that cause up to 250,000 deaths annually, thus emphasizing the need for drugs with new mechanisms of action. Recently, the natural product chrysomycin A was identified as having potent anti-TB activity in a high-throughput screen (MIC = 0.4 µg/mL against MDR-TB). Chrysomycin A is a rare C-aryl glycoside whose yields via fermentation from its natural source are insufferably low.  To provide sufficient materials for biological testing, the group of Xiaoguang Lei devised a total synthesis route to chrysomycin A ( 1 ), its natural congeners polycarcin V ( 8 ) and gilvocarcin V ( 10 , Figure 1 ), and 33 new analogues.  The preparation of a late-stage intermediate that is amenable to d...

Triple-negative breast cancers (TNBCs), defined by lack of expression of estrogen receptor, progesterone receptor and HER2, account for 12-17% of breast cancers and are clinically perceived as a discrete breast cancer subgroup. Despite an aggressive approach in the management of TNBCs with current therapy, the recurrence and 5-year survival rates for TNBC stand at 50% and 37%, respectively. Therefore, for doctors and researchers, there is tense interest in finding new medications that can treat this kind of breast cancer more efficiently.  E74-like transcription factor (Elf5) functions as a suppressor of epithelial-to-mesenchymal transition (EMT), a characteristic that imparts the tumor’s invasive and metastatic properties. Snahlata Singh et al. found that the loss of Elf5 increases tumor burden, growth and metastasis by activating intrinsic interferon- γ (IFN-γ), a cytokine that is both anti- and pro-tumorigenic. Mechanistically, they discovered that Elf5 inhibits IFN-γ sign...

One of the most common ways to study biomolecules is to label specific amino acids, mostly cysteine, with chemical handles for further modification. Azide-alkyne click reaction is a very popular strategy due to its high reactivity and reaction rate. Therefore, numerous reagents have been developed to specifically label proteins with terminal alkynes, including iodoacetamide alkynes and maleimide derivatives. However, limitations like insufficient selectivity and low stability remain as long-lasting concerns. To address these problems, one common strategy is introducing a linker between the targeting residue and the alkyne moiety , which potentially brings in unwanted structural changes. A reagent that can introduce small-sized terminal alkyne with one step under mild conditions is in demand. Scheme 1 . Cysteine-labeling study in this work In this study, the Waser group presented a series of reagents that selectively ethynylate cysteine in a one-pot manner ( Scheme 1 ). The ...

The COVID-19 pandemic caused by the SARS-CoV-2 virus has become an unprecedented global crisis, with so far over 4.1 million infections and 283,000 deaths reported. SARS-CoV-2 is a positive strand RNA virus, and its replication is dependent on RNA polymerase (RdRp) consisting of nsp12, nsp7, and nsp8. However, the lack of structure of RdRp in complex with an RNA or with nucleotide inhibitors hampers drug development. Recently, a joint research group from China successfully determined the cryo-EM structure of the SARS-CoV-2 RdRp complex with a template-primer RNA and the antiviral drug Remdesivir, which was recently received the Emergency Use Authorization (EUA) status for COVID-19 from the FDA. In the co-structure, the template-RTP RdRp complex contains one nsp12, one nsp7 and one nsp8, and the template-primer RNA consisting of a 14-base RNA in the template strand, a 11-base RNA in the primer strand held by the finger-palm-thumb subdomains (Figure 1A). The template-primer RNA form...

Tuberculosis (TB) is one of the world’s leading causes of death from a single infectious agent, second to human immunodeficiency virus (HIV). However, TB-HIV co-infection is a serious problem because current TB drugs (such as rifampin) induce hepatic metabolic enzymes (such as CYP2C9 and CYP3A4) that degrade anti-retroviral drugs, which in turn renders patients in an immunocompromised state that accelerates the progression of their TB. In their search for new anti-TB drug leads that do not induce CYP activation, the Looper group and collaborators identified the known natural product amicetin ( Figure 1 ) and found that it possesses potent anti-TB activity (IC 50 = 0.24 µm), but less than 3-fold induction of CYP3A4 and CYP2D6 (rifampin induction levels are 47- and 6-fold, respectively). Therefore, the group decided to utilize to modify the pharmacophore of this natural product to address the need for new TB therapies. Although amicetin and its natural relatives have been shown to ...

With the development of immune checkpoint inhibitors targeting PD-1/PD-L1 and CTLA-4, immunotherapy has emerged as a highly promising approach to revolutionize cancer treatments. Certain tumor types exhibit remarkable clinical responses to immunotherapy, in particular melanoma, non-small cell lung cancer and colon cancer. However, for most patients with common cancer types, including breast and ovarian cancers, are less likely to respond to immunotherapy and less than 13% of cancer patients respond to immune checkpoint inhibitors alone. Based on their long-standing interest in identifying mechanisms that would enhance cancer response to the combination of immune checkpoint blockade and chemotherapy, Sriram et al. took advantage of the “cross-talk” between the DNA damage response and signalling pathways that mediate tumor cell survival and death to enhance anti-tumor immune responses.  Sriram et al. treated B16-Ova melanoma cells with clinically used chemotherapeutic agents...

Prostate cancer is the second most common cancer affecting males in the   United   States . Hormone therapy has been widely used for prostate cancer treatment, such as androgen deprivation and targeting androgen receptor with small molecules. However, under long-term treatment, patients develop castration-resistant prostate cancer (CRPC) an d eventually die. Therefore, it’s urgent to discover novel therapeutic targets to improve prostate cancer treatment. In 2013, the Tsai group identified that COUP-TFII, an orphan nuclear receptor whose overexpression involving in multiple diseases, can serve as a potential drug target for prostate cancer. Recently, the Tsai group further developed novel small molecule inhibitors, CIA1 and CIA2 , directly targeting COUPTF-II for prostate cancer treatment. CIA1 and CIA2 were obtained through a high-throughput screening. They are specific inhibitors targeting COUP-TFII: i) The inhibitors reduce the prostate cell growth while...

As 95% of human genes are alternatively spliced, abnormal splicing events are the common causes of many pathological conditions, including most neurodegenerative diseases. Therapeutic interventions have been developed to target RNAs, such as antisense oligonucleotides, one of which was recently approved by FDA to treat spinal muscular atrophy. Despite high potency and selectivity, current applications of antisense oligonucleotides are impeded by their limited tissue distribution. Directly targeting RNA with small molecules can serve as a promising alternative approach that can achieve systemic distribution. Figure 1 .  An Inforna-based search of a database of RNA−small-molecule interactions that target the SRE led to the identification of compounds  1  to  4 . Here in this study, the Disney group developed a series of small molecules directly targeting tau pre-mRNA based on its sequence. Tau protein is one of the most popular targets for neurodegenerat...