根據先前的研究，純化Naja atra蛇毒過程中，觀察到高分子量的蛋白，經由純化後，得到蛇毒磷酸二酯酶 (svPDE) 的醣蛋白，並且不帶有毒性，svPDE的功能尚未被徹底研究，因此想知道在蛇毒中是否扮演特別的角色。svPDE催化活性口袋的結構中帶有兩顆鋅離子，和Insert loop構成活性催化域；在演化上，藉由胺基酸的比對，發現與人類ENPP1和ENPP3蛋白家族很類似，並且與ENPP3為同源物。一種稱為cGAS-STING的先天性免疫反應，cGAS會將DNA合成為2’, 3’-cGAMP，並活化該系統，其中人類ENPP1在許多文獻中被發現，能夠水解2’, 3’-cGAMP，對於cGAS-STING有著負向調控的功能。因此我們猜測當被蛇咬傷時，被破壞細胞的DNA或粒線體DNA漏出，雖然活化了cGAS-STING pathway，但是因為svPDE的干擾導致免疫反應無法正常運作。在我的研究中，確認svPDE會水解2’, 3’-cGAMP，模擬出來的對接結果顯示Tyr456在GMP位置可能起到很重要的作用。我認為若是svPDE能夠水解2’, 3’-cGAMP，也許能透過抑制人類先天免疫反應，促進蛇毒在人類免疫系統的擴散。同時利用先前研究出svPDE的小分子抑制劑，觀察是否能抑制svPDE水解2’, 3’-cGAMP。

Snake venom phosphodiesterase (svPDE) from Naja atra revealed that the svPDE evolved from ENPP3 (Pan et al., 2023), but the function of svPDE is not clear. SvPDE is a high molecular weight glycoprotein, generally present in various kinds of snake venom. Sequence alignment showed that svPDE is homologous to human ENPP3, ENPP family can hydrolyze nucleotides and derivatives. Recent research has shown that human ENPP1 can hydrolyze 2’, 3’-cyclic GMP–AMP (cGAMP) (Carozza et al., 2022). 2’, 3’-cGAMP plays an important role as a secondary messenger. The inactive stimulator of interferon genes (STING) is a dimer, upon cGAMP binding, STING molecules become oligomers, activating interferon production (Li et al., 2018). cGAS can sense dsDNA and synthesize 2’, 3’-cGAMP. In my study, we aim to investigate whether svPDE can also hydrolyze 2’, 3’-cGAMP.
In my research, it was confirmed that svPDE can hydrolyze 2’, 3’-cGAMP, and the simulated docking results showed that Tyr456 may play an important role at the GMP position. I think that if svPDE can hydrolyze 2’, 3’-cGAMP, it may be able to promote the spread of snake venom in the human immune system by inhibiting the human innate immune response. At the same time, using the small molecule inhibitors of svPDE previously developed to observe whether it can inhibit the hydrolysis of 2’, 3’-cGAMP by svPDE. According to our results, Quercetin inhibits the hydrolysis of cGAMP by svPDE, which can provide therapeutics for modulating the immune response of the prey upon snakebites.

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