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The discovery of cancer dependencies has the potential to inform therapeutic strategies and to identify putative drug targets. Integrating data from comprehensive genomic profiling of cancer cell lines and from functional characterization of cancer cell dependencies, we discovered that loss of the enzyme methylthioadenosine phosphorylase (MTAP) confers a selective dependence on protein arginine methyltransferase 5 (PRMT5) and its binding partner WDR77. MTAP is frequently lost due to its proximity to the commonly deleted tumor suppressor gene, CDKN2A. We observed increased intracellular concentrations of methylthioadenosine (MTA, the metabolite cleaved by MTAP) in cells harboring MTAP deletions. Furthermore, MTA specifically inhibited PRMT5 enzymatic activity. Administration of either MTA or a small-molecule PRMT5 inhibitor showed a modest preferential impairment of cell viability for MTAP-null cancer cell lines compared with isogenic MTAP-expressing counterparts. Together, our findings reveal PRMT5 as a potential vulnerability across multiple cancer lineages augmented by a common \"passenger\" geomic alteration.

Adenosine deaminase (ADA) is one of the most important enzymes in nucleoside metabolism, regulating the levels of adenosine and deoxyadenosine triphosphate (ADT/dATP) on either side of the cell membrane. This small protein (weighing approximately 40 kDa) exhibits deamination properties towards other pharmaceuticals built on adenine as the leading structure, which requires co-administration of ADA inhibitors. 3′-deoxyadenosine (Cordycepin, Cord) is an active compound isolated from the fungus Cordyceps, which has been used in traditional Chinese medicine for over 2000 years. Its anticancer activity is likely related to the inhibition of primer elongation of lagging strands during genetic information replication. Unfortunately, Cord is rapidly deaminated by ADA into inactive 3′-deoxyinosine, necessitating its co-administration with ADA inhibitors. Here, for the first time, the synthesis and discussion of the oxidised form of Cord are presented. The 7,8-dihydro-8-oxo-3′-deoxyadenosine (CordOXO) exhibits high resistance to ADA because of its syn conformation, as shown experimentally by UV spectroscopy and RP-HPLC monitoring. Theoretical Density Functional based Tight Binding (DFTB) studies of the Michaelis complex ADA-CordOXO have revealed significant distance increases between the “active” H2O molecule and C6 of the 8-oxo-adenine moiety of CordOXO, i.e., 4 Å as opposed to 2.7 Å in the cases of ADA-dAdo and Cord. In conclusion, it can be postulated that the conversion of Cord to CordOXO enhances its therapeutic potential; however, this needs to be verified in vitro and in vivo. It should be emphasised that the therapeutic effect, if any, can be achieved theoretically without ADA inhibitors, e.g., pentostatin, thus reducing adverse effects. These promising preliminary results, presented here, warrant further investigations.

The pathological mechanisms of radiation ulcer remain unsolved and there is currently no effective medicine. Here, we demonstrate that persistent DNA damage foci and cell senescence are involved in radiation ulcer development. Further more, we identify cordycepin, a natural nucleoside analogue, as a potent drug to block radiation ulcer (skin, intestine, tongue) in rats/mice by preventing cell senescence through the increase of NRF2 nuclear expression (the assay used is mainly on skin). Finally, cordycepin is also revealed to activate AMPK by binding with the α1 and γ1 subunit near the autoinhibitory domain of AMPK, then promotes p62-dependent autophagic degradation of Keap1, to induce NRF2 dissociate from Keap1 and translocate to the nucleus. Taken together, our findings identify cordycepin prevents radiation ulcer by inhibiting cell senescence via NRF2 and AMPK in rodents, and activation of AMPK or NRF2 may thus represent therapeutic targets for preventing cell senescence and radiation ulcer. Radiation damage causes DNA foci to form and senescence, causing ulcers. Here, the authors show that a naturally occurring adenosine analogue, cordycepin, prevents cell senescence via an increase in AMPK/NRF2, so blocking ulcers caused by radiation on skin/intestine/tongue damage in rodents.

Nucleoside reverse transcriptase translocation inhibitors (NRTTIs) are potent antiretroviral agents that block HIV replication. A comprehensive lead optimization campaign was undertaken to develop a novel long-acting NRTTI with the potential for extended-duration dosing for HIV prophylaxis. Broad exploration of nucleoside structure–activity relationship (SAR), leveraging ribose core, periphery, and nucleobase modifications, along with systematic progression of compounds of interest through key in vitro and in vivo studies led to the discovery of MK-8527. MK-8527 is a novel deoxyadenosine analog that is phosphorylated intracellularly to its active triphosphate (TP) form, which inhibits reverse transcription. Iron footprinting and primer extension assays demonstrated that MK-8527-TP inhibits translocation of reverse transcriptase on the primer and template, and this inhibition allows for both immediate and delayed chain termination of reverse transcription. MK-8527 inhibits viral replication in human peripheral blood mononuclear cells (PBMCs), with a half maximal inhibitory concentration (IC 50 ) of 0.21 nM. The pharmacokinetic (PK) profile of MK-8527 in rats and rhesus monkeys was characterized by low-to-moderate clearance and volume of distribution, with good oral absorption (57% and 100% in rats and monkeys, respectively). Following oral administration of MK-8527 to monkeys, MK-8527-TP exhibited an intracellular half-life of approximately 48 h in PBMCs, significantly longer than the apparent plasma half-life of the parent compound (approximately 7 h). MK-8527 and MK-8527-TP demonstrated favorable in vitro off-target profiles, with IC 50 values of ≥95 µM against human DNA polymerases tested, and no off-target activities at 10 μM against a panel of 114 enzyme and receptor binding assays. Collectively, the potent antiretroviral activity and favorable preclinical PK and off-target profiles make MK-8527 an attractive clinical candidate, and it is currently in clinical trials for once-monthly oral HIV-1 pre-exposure prophylaxis.

Background The secondary injury caused by traumatic brain injury (TBI), especially white matter injury (WMI), is highly sensitive to neuroinflammation, which further leads to unfavored long-term outcomes. Although the cross-talk between the three active events, immune cell infiltration, BBB breakdown, and proinflammatory microglial/macrophage polarization, plays a role in the vicious cycle, its mechanisms are not fully understood. It has been reported that cordycepin, an extract from Cordyceps militaris , can inhibit TBI-induced neuroinflammation although the long-term effects of cordycepin remain unknown. Here, we report our investigation of cordycepin’s long-term neuroprotective function and its underlying immunological mechanism. Methods TBI mice model was established with a controlled cortical impact (CCI) method. Cordycepin was intraperitoneally administered twice daily for a week. Neurological outcomes were assessed by behavioral tests, including grid walking test, cylinder test, wire hang test, and rotarod test. Immunofluorescence staining, transmission electron microscopy, and electrophysiology recording were employed to assess histological and functional lesions. Quantitative-PCR and flow cytometry were used to detect neuroinflammation. The tracers of Sulfo-NHS-biotin and Evans blue were assessed for the blood-brain barrier (BBB) leakage. Western blot and gelatin zymography were used to analyze protein activity or expression. Neutrophil depletion in vivo was performed via using Ly6G antibody intraperitoneal injection. Results Cordycepin administration ameliorated long-term neurological deficits and reduced neuronal tissue loss in TBI mice. Meanwhile, the long-term integrity of white matter was also preserved, which was revealed in multiple dimensions, such as morphology, histology, ultrastructure, and electrical conductivity. Cordycepin administration inhibited microglia/macrophage pro-inflammatory polarization and promoted anti-inflammatory polarization after TBI. BBB breach was attenuated by cordycepin administration at 3 days after TBI. Cordycepin suppressed the activities of MMP-2 and MMP-9 and the neutrophil infiltration at 3 days after TBI. Moreover, neutrophil depletion provided a cordycepin-like effect, and cordycepin administration united with neutrophil depletion did not show a benefit of superposition. Conclusions The long-term neuroprotective function of cordycepin via suppressing neutrophil infiltration after TBI, thereby preserving BBB integrity and changing microglia/macrophage polarization. These findings provide significant clinical potentials to improve the quality of life for TBI patients.

4′-Ethynyl-2-fluoro-2′-deoxyadenosine (EFdA) is the most potent nucleoside analog inhibitor of HIV reverse transcriptase (RT). It retains a 3′-OH yet acts as a chain-terminating agent by diminishing translocation from the pretranslocation nucleotide-binding site (N site) to the posttranslocation primer-binding site (P site). Also, facile misincorporation of EFdA-monophosphate (MP) results in difficult-to-extend mismatched primers. To understand the high potency and unusual inhibition mechanism of EFdA, we solved RT crystal structures (resolutions from 2.4 to 2.9 Å) that include inhibition intermediates (i) before inhibitor incorporation (catalytic complex, RT/DNA/EFdA-triphosphate), (ii) after incorporation of EFdA-MP followed by dT-MP (RT/DNAEFdA-MPP•dT-MPN ), or (iii) after incorporation of two EFdA-MPs (RT/DNAEFdA-MPP•EFdA-MPN ); (iv) the latter was also solved with EFdA-MP mismatched at the N site (RT/DNAEFdA-MPP•EFdA-MP*N ). We report that the inhibition mechanism and potency of EFdA stem from interactions of its 4′-ethynyl at a previously unexploited conserved hydrophobic pocket in the polymerase active site. The high resolution of the catalytic complex structure revealed a network of ordered water molecules at the polymerase active site that stabilize enzyme interactions with nucleotide and DNA substrates. Finally, decreased translocation results from favorable interactions of primer-terminating EFdA-MP at the pretranslocation site and unfavorable posttranslocation interactions that lead to observed localized primer distortions.

Cordyceps is a genus of ascomycete fungi that has been used for traditional herbal remedies. It contains various bioactive ingredients including cordycepin. Cordycepin, also known as 3-deoxyadenosine, is a major compound and has been suggested to have anticancer potential. The treatment of various cancer cells with cordycepin in effectively induces cell death and retards their cancerous properties. However, the underlying mechanism is not fully understood. Recent evidence has shed light on the molecular pathways involving cysteine-aspartic proteases (caspases), mitogen-activated protein kinases (MAPKs), and glycogen synthase kinase 3 beta (GSK-3β). Furthermore, the pathways are mediated by putative receptors, such as adenosine receptors (ADORAs), death receptors (DRs), and the epidermal growth factor receptor (EGFR). This review provides the molecular mechanisms by which cordycepin functions as a singular or combinational anticancer therapeutic agent.

African trypanosomiasis is a disease caused by Trypanosoma brucei parasites with limited treatment options. Trypanosoma is unable to synthesize purines de novo and relies solely on their uptake and interconversion from the host, constituting purine nucleoside analogues a potential source of antitrypanosomal agents. Here we combine structural elements from known trypanocidal nucleoside analogues to develop a series of 3’-deoxy-7-deazaadenosine nucleosides, and investigate their effects against African trypanosomes. 3’-Deoxytubercidin is a highly potent trypanocide in vitro and displays curative activity in animal models of acute and CNS-stage disease, even at low doses and oral administration. Whole-genome RNAi screening reveals that the P2 nucleoside transporter and adenosine kinase are involved in the uptake and activation, respectively, of this analogue. This is confirmed by P1 and P2 transporter assays and nucleotide pool analysis. 3’-Deoxytubercidin is a promising lead to treat late-stage sleeping sickness. Trypanosoma brucei relies on uptake and conversion of purines from the host, which constitutes a potential drug target. Here, Hulpia et al . combine structural elements from known trypanocidal nucleoside analogues and develop a potent trypanocide with curative activity in animal models of acute and late stage sleeping sickness.

There is currently much interest in finding new phytochemicals among plants and fungi as nature-based alternatives to replace problematic herbicides such as glyphosate, which are preferentially used in agricultural production. We discovered striking herbicidal potency in Cordyceps militaris (L.) and identified cordycepin as its principal plant growth inhibitor. Cordycepin obtained as an ethyl acetate extract was subjected to column chromatography and evaluated for its bioassay-guided phytotoxic capacity against Raphanus sativus (radish), showing a maximum inhibition on germination and growth of radish (IC50 = 0.052–0.078 mg/mL). Gas chromatography-mass spectrometry (GC-MS) (m/z: 251.2) and liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) ([M + Na]+ m/z: 274.1; [M + H]+ m/z: 252.1) analyses confirmed cordycepin as the major component of the tested column fraction (55.38%). At 0.04 mg/mL, cordycepin showed 3.8–5.9- and 3.3–3.7-fold greater inhibition of the germination and growth of radish than benzoic acid (BA) and glyphosate, respectively. Compared with BA, isolated cordycepin reduced plant chlorophyll and carotenoid contents (2.0–9.5 -fold), while proline, total phenolic and total flavonoid contents were increased 1.2–1.8-fold. Finally, cordycepin promoted electrolyte leakage and malondialdehyde accumulation in radish aerial parts. Thus, cordycepin successfully isolated from Cordyceps militaris is a highly potent plant growth inhibitor with pending worldwide patent and may become a potential plant-based novel alternative to the disputed glyphosate.

To verify whether the recently synthesized nucleoside, 8-(4-Trifluoromethoxy)benzylamino-2′-deoxyadenosine, can sensitize tumorous cells to X-rays, radiolytic and in vitro studies have been conducted. Molecular modeling demonstrated that excess electrons should lead to efficient dissociative electron attachment (DEA) to dA-NHbenzylOCF 3 resulting in a radical product that can potentially damage DNA. The computationally predicted DEA process was confirmed via stationary radiolysis of a dA-NHbenzylOCF 3 water solution followed by LC-MS analysis of the obtained radiolytes. Moreover, dA-NHbenzylOCF 3 was tested against its cytotoxicity and clonogenicity. We showed that the modified nucleoside is not cytotoxic to PC3, MCF-7, and HaCaT cell lines. Additionally, the clonogenic test exhibited a statistically significant radiosensitization of PC3 and MCF-7 cells to X-rays. On the other hand, flow cytometry assays demonstrated that the action of dA-NHbenzylOCF 3 is related to its influence on the cell cycle rather than the level of DNA double-strand breaks induced by ionizing radiation. Our findings indicate that the compound enters the cell and predominantly localizes in the cytoplasm, with a notable amount also detected in the nucleus. Moreover, we established that the compound is not phosphorylated by cellular kinases nor integrated into genomic DNA by the replication machinery.