Journal Articles

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    Synthesis of 1,4-azaphosphinine nucleosides and evaluation as inhibitors of human cytidine deaminase and APOBEC3A.
    (Beilstein-Institut, 2024-05-15) Kvach MV; Harjes S; Kurup HM; Jameson GB; Harjes E; Filichev VV; Allen KN
    Nucleoside and polynucleotide cytidine deaminases (CDAs), such as CDA and APOBEC3, share a similar mechanism of cytosine to uracil conversion. In 1984, phosphapyrimidine riboside was characterised as the most potent inhibitor of human CDA, but the quick degradation in water limited the applicability as a potential therapeutic. To improve stability in water, we synthesised derivatives of phosphapyrimidine nucleoside having a CH2 group instead of the N3 atom in the nucleobase. A charge-neutral phosphinamide and a negatively charged phosphinic acid derivative had excellent stability in water at pH 7.4, but only the charge-neutral compound inhibited human CDA, similar to previously described 2'-deoxyzebularine (Ki = 8.0 ± 1.9 and 10.7 ± 0.5 µM, respectively). However, under basic conditions, the charge-neutral phosphinamide was unstable, which prevented the incorporation into DNA using conventional DNA chemistry. In contrast, the negatively charged phosphinic acid derivative was incorporated into DNA instead of the target 2'-deoxycytidine using an automated DNA synthesiser, but no inhibition of APOBEC3A was observed for modified DNAs. Although this shows that the negative charge is poorly accommodated in the active site of CDA and APOBEC3, the synthetic route reported here provides opportunities for the synthesis of other derivatives of phosphapyrimidine riboside for potential development of more potent CDA and APOBEC3 inhibitors.
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    Pathogenicity of Beauveria bassiana PfBb and Immune Responses of a Non-Target Host, Spodoptera frugiperda (Lepidoptera: Noctuidae)
    (MDPI AG, 8/10/2022) Gao Y-P; Luo M; Wang X-Y; He X; Lu W; Zheng X-L
    Exploring the pathogenicity of a new fungus strain to non-target host pests can provide essential information on a large scale for potential application in pest control. In this study, we tested the pathogenicity of Beauveria bassiana PfBb on the important agricultural pest Spodoptera frugiperda (Lepidoptera: Noctuidae) by determining the relative activities of protective enzymes and detoxifying enzymes in different larval instars. Our results show that the B. bassiana PfBb strain could infect all six larval instars of S. frugiperda, and its virulence to S. frugiperda larvae gradually increased with an increase in spore concentration. Seven days after inoculation, the LC50 of B. bassiana PfBb was 7.7 × 105, 5.5 × 106, 2.2 × 107, 3.1 × 108, 9.6 × 108, and 2.5 × 1011 spores/mL for first to sixth instars of S. frugiperda, respectively, and the LC50 and LC90 of B. bassiana PfBb for each S. frugiperda instar decreased with infection time, indicating a significant dose effect. Furthermore, the virulence of B. bassiana PfBb to S. frugiperda larvae gradually decreased with an increase in larval instar. The activities of protective enzymes (i.e., catalase, peroxidase, and superoxide dismutase) and detoxifying enzymes (i.e., glutathione S-transferases, carboxylesterase, and cytochrome P450) in S. frugiperda larvae of the first three instars infected with B. bassiana PfBb changed significantly with infection time, but such variations were not obvious in the fifth and sixth instars. Additionally, after being infected with B. bassiana PfBb, the activities of protective enzymes and detoxification enzymes in S. frugiperda larvae usually lasted from 12 to 48 h, which was significantly longer than the control. These results indicate that the pathogenicity of B. bassiana PfBb on the non-target host S. frugiperda was significant but depended on the instar stage. Therefore, the findings of this study suggest that B. bassiana PfBb can be used as a bio-insecticide to control young larvae of S. frugiperda in an integrated pest management program.