Histone deacetylase 11 (HDAC11), an enzyme that cleaves acyl groups from acylated lysine residues, is the sole member of class IV of HDAC family with no reported crystal structure so far. The catalytic domain of HDAC11 shares low sequence identity with other HDAC isoforms which complicates the conventional template-based homology modeling. AlphaFold is a neural network machine learning approach for predicting the 3D structures of proteins with atomic accuracy even in absence of similar structures. However, the structures predicted by AlphaFold are missing small molecules as ligands and cofactors. In our study, we first optimized the HDAC11 AlphaFold model by adding the catalytic zinc ion followed by assessment of the usability of the model by docking of the selective inhibitor FT895. Minimization of the optimized model in presence of transplanted inhibitors, which have been described as HDAC11 inhibitors, was performed. Four complexes were generated and proved to be stable using three replicas of 50 ns MD simulations and were successfully utilized for docking of the selective inhibitors FT895, MIR002 and SIS17. For SIS17, The most reasonable pose was selected based on structural comparison between HDAC6, HDAC8 and the HDAC11 optimized AlphaFold model. The manually optimized HDAC11 model is thus able to explain the binding behavior of known HDAC11 inhibitors and can be used for further structure-based optimization.

2022-03-01·Insect Biochemistry and Molecular Biology1区 · 农林科学

Temporal analysis of microRNAs associated with wing development in the English grain aphid, Sitobion avenae (F.) (Homoptera: Aphidiae)

1区 · 农林科学

Article

作者: Zhu, Xun ; Li, Xiangrui ; Wei, Changping ; Zhou, Xuguo ; Zhang, Fangmei ; Zhang, Yunhui ; Coates, Brad

Molecular mechanisms underlying wing evolution and development have been a point of scientific inquiry for decades. Phloem-feeding aphids are one of the most devastating global insect pests, where dispersal of winged morphs lead to annual movements, migrations, and range expansions. Aphids show a polyphenic wing dimorphism trait, and offer a model to study the role of environment in determining morphological plasticity of a single genotype. Despite recent progresses in the genetic understanding of wing polyphenism, the influence of environmental cues remains unclear. To investigate the involvement of miRNAs in wing development, we sequenced small RNA libraries of the English grain aphid, Sitobion avenae (F.) across six different developmental stages. As a result, we identified 113 conserved and 193 S. avenae-specific miRNAs. Gene Ontology and KEGG pathway analyses of putative target mRNAs for the six differentially expressed miRNAs are enriched for wing development processes. Dietary uptake of miR-263a, miR-316, and miR-184a agomirs and antagomirs led to significantly higher mortality (>70%) and a lower proportion of winged morphs (<5%). On the other hand, wing malformation was observed in miR-2 and miR-306 agomirs and miR-2 and miR-14 antagomirs, respectively, suggesting their involvement in S. avenae wing morphogenesis. These combined results not only shed light on the regulatory role of miRNAs in wing dimorphism, but also provide potential novel targets for the long-term sustainable management of S. avenae, a devastating global grain pest.

2022-01-01·European Journal of Medicinal Chemistry1区 · 医学

Antitumor activity of novel POLA1-HDAC11 dual inhibitors

1区 · 医学

Article

作者: Colelli, Fabiana ; La Porta, Ilaria ; Cardile, Francesco ; Riccio, Assunta ; Fucci, Alessandra ; Vistoli, Giulio ; Musso, Loana ; Darwiche, Nadine ; Modica, Elisa ; Pisano, Claudio ; Guglielmi, Mario B ; Signorino, Giacomo ; Pizzulo, Maddalena ; Prosperi, Federica ; Dallavalle, Sabrina ; Cincinelli, Raffaella ; Gervasoni, Silvia ; D'Andrea, Egildo Luca

Hybrid molecules targeting simultaneously DNA polymerase α (POLA1) and histone deacetylases (HDACs) were designed and synthesized to exploit a potential synergy of action. Among a library of screened molecules, MIR002 and GEM144 showed antiproliferative activity at nanomolar concentrations on a panel of human solid and haematological cancer cell lines. In vitro functional assays confirmed that these molecules inhibited POLA1 primer extension activity, as well as HDAC11. Molecular docking studies also supported these findings. Mechanistically, MIR002 and GEM144 induced acetylation of p53, activation of p21, G1/S cell cycle arrest, and apoptosis. Oral administration of these inhibitors confirmed their antitumor activity in in vivo models. In human non-small cancer cell (H460) xenografted in nude mice MIR002 at 50 mg/kg, Bid (qd × 5 × 3w) inhibited tumor growth (TGI = 61%). More interestingly, in POLA1 inhibitor resistant cells (H460-R9A), the in vivo combination of MIR002 with cisplatin showed an additive antitumor effect with complete disappearance of tumor masses in two animals at the end of the treatment. Moreover, in two human orthotopic malignant pleural mesothelioma xenografts (MM473 and MM487), oral treatments with MIR002 and GEM144 confirmed their significant antitumor activity (TGI = 72-77%). Consistently with recent results that have shown an inverse correlation between POLA1 expression and type I interferon levels, MIR002 significantly upregulated interferon-α in immunocompetent mice.

100 项与 MIR-002 相关的药物交易

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