tetano
Editor, Senior Moderator
Eur J Med Chem
. 2024 Oct 28:281:117004.
doi: 10.1016/j.ejmech.2024.117004. Online ahead of print. Discovery of peptidomimetic spiropyrrolidine derivatives as novel 3CL[SUP]pro[/SUP] inhibitors against SARS-CoV -2
Samuel Desta Guma[SUP] 1 [/SUP], Zhaoyin Zhou[SUP] 2 [/SUP], Kang Song[SUP] 3 [/SUP], Feipu Yang[SUP] 4 [/SUP], Jin Suo[SUP] 4 [/SUP], Yan Zhang[SUP] 4 [/SUP], Emmanuel Mintah Bonku[SUP] 1 [/SUP], Abdullajon Odilov[SUP] 1 [/SUP], Guanghui Tian[SUP] 5 [/SUP], Zhijian Xu[SUP] 6 [/SUP], Xiangrui Jiang[SUP] 7 [/SUP], Qiumeng Zhang[SUP] 8 [/SUP], Weiliang Zhu[SUP] 9 [/SUP], Jingshan Shen[SUP] 10 [/SUP]
Affiliations
Given the high pathogenicity and rapid mutation rates of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it is imperative to sustain efforts in drug research and development. Herein, we present the design, synthesis, and evaluation of peptidomimetic spiropyrrolidine derivatives as potent 3CL[SUP]pro[/SUP] inhibitors against SARS-CoV-2. Among the synthesized derivatives, several compounds exhibited high potency in inhibiting 3CL[SUP]pro[/SUP], with IC[SUB]50[/SUB] values ranging from 21 nM to 53 nM. Notably, compounds 9b and 9h displayed improved enzymatic inhibition (IC[SUB]50[/SUB] = 25 nM and 21 nM, respectively) compared to nirmatrelvir (47 nM). Compound 9b showed enhanced stability in human and mouse liver microsomes compared to nirmatrelvir, whereas 9h exhibited similar stability to nirmatrelvir in both species. Furthermore, compound 9h displayed exceptional potency in cellular assays targeting the SARS-CoV-2 replicon within Huh7 cells, with a single-digit nanomolar activity that is 5.6 times better than that of nirmatrelvir. In a pharmacokinetic study in mice (PO, 20 mg/kg), compound 9h exhibited a prolonged plasma half-life (T[SUB]1/2[/SUB] = 2.58 h) compared to nirmatrelvir (T[SUB]1/2[/SUB] = 0.51 h) and demonstrated an AUC[SUB](0-t)[/SUB] value (1106 h∗ng/mL) equivalent to that of nirmatrelvir (1023 h∗ng/mL). These findings indicate that compound 9h is a promising lead for developing a novel 3CL[SUP]pro[/SUP] inhibitor against SARS-CoV-2.
Keywords: 3CL(pro) inhibitors; Peptidomimetics; SARS-CoV-2; Spiropyrrolidine derivatives.
. 2024 Oct 28:281:117004.
doi: 10.1016/j.ejmech.2024.117004. Online ahead of print. Discovery of peptidomimetic spiropyrrolidine derivatives as novel 3CL[SUP]pro[/SUP] inhibitors against SARS-CoV -2
Samuel Desta Guma[SUP] 1 [/SUP], Zhaoyin Zhou[SUP] 2 [/SUP], Kang Song[SUP] 3 [/SUP], Feipu Yang[SUP] 4 [/SUP], Jin Suo[SUP] 4 [/SUP], Yan Zhang[SUP] 4 [/SUP], Emmanuel Mintah Bonku[SUP] 1 [/SUP], Abdullajon Odilov[SUP] 1 [/SUP], Guanghui Tian[SUP] 5 [/SUP], Zhijian Xu[SUP] 6 [/SUP], Xiangrui Jiang[SUP] 7 [/SUP], Qiumeng Zhang[SUP] 8 [/SUP], Weiliang Zhu[SUP] 9 [/SUP], Jingshan Shen[SUP] 10 [/SUP]
Affiliations
- PMID: 39504795
- DOI: 10.1016/j.ejmech.2024.117004
Given the high pathogenicity and rapid mutation rates of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it is imperative to sustain efforts in drug research and development. Herein, we present the design, synthesis, and evaluation of peptidomimetic spiropyrrolidine derivatives as potent 3CL[SUP]pro[/SUP] inhibitors against SARS-CoV-2. Among the synthesized derivatives, several compounds exhibited high potency in inhibiting 3CL[SUP]pro[/SUP], with IC[SUB]50[/SUB] values ranging from 21 nM to 53 nM. Notably, compounds 9b and 9h displayed improved enzymatic inhibition (IC[SUB]50[/SUB] = 25 nM and 21 nM, respectively) compared to nirmatrelvir (47 nM). Compound 9b showed enhanced stability in human and mouse liver microsomes compared to nirmatrelvir, whereas 9h exhibited similar stability to nirmatrelvir in both species. Furthermore, compound 9h displayed exceptional potency in cellular assays targeting the SARS-CoV-2 replicon within Huh7 cells, with a single-digit nanomolar activity that is 5.6 times better than that of nirmatrelvir. In a pharmacokinetic study in mice (PO, 20 mg/kg), compound 9h exhibited a prolonged plasma half-life (T[SUB]1/2[/SUB] = 2.58 h) compared to nirmatrelvir (T[SUB]1/2[/SUB] = 0.51 h) and demonstrated an AUC[SUB](0-t)[/SUB] value (1106 h∗ng/mL) equivalent to that of nirmatrelvir (1023 h∗ng/mL). These findings indicate that compound 9h is a promising lead for developing a novel 3CL[SUP]pro[/SUP] inhibitor against SARS-CoV-2.
Keywords: 3CL(pro) inhibitors; Peptidomimetics; SARS-CoV-2; Spiropyrrolidine derivatives.