Your browser doesn't support javascript.
DESIGN of NOVEL and HIGHLY SELECTIVE SARS-CoV-2 MAIN PROTEASE INHIBITORS
Topics in Antiviral Medicine ; 30(1 SUPPL):182, 2022.
Article in English | EMBASE | ID: covidwho-1880819
ABSTRACT

Background:

SARS-CoV-2 has caused a global pandemic, yet despite vaccine availability, it continues to inflict morbidity and mortality worldwide. The viral main protease (Mpro) is highly conserved across multiple coronaviruses and has a unique viral substrate specificity. Thus, highly selective Mpro inhibitors are expected to be safe, effective, and elude drug resistance for future coronaviruses.

Methods:

We used a conformationally restricted peptidomimetic to mimic the bioactive conformation of the Mpro-substrate complex to identify potent, selective Mpro inhibitors. We evaluated protease inhibition in biochemical assays, and cellular efficacy in Vero-E6 cells challenged with live virus representing parental (USA-WA1/2020), beta (B.1.351), and delta (B.1.617.2) variants by monitoring infection at day 2 post-infection measuring nucleocapsid-positive cells by high content imaging, and cytopathic effect (CPE) at day 4 post-infection using resazurin viability dye. Results were compared to reference compounds. Group differences were analyzed by two-sided, paired t-test.

Results:

AP-8-013 required a 2-hour incubation to achieve maximal dose-dependent Mpro inhibition with an IC50 = 230 ± 18 nM, reflecting its highly constrained conformation, compared to the more flexible Cpd 22 (AP-8-001;IC50 = 11 ± 0.7 nM) or GC-376 (IC50 = 18 ± 1.5 μM). Importantly, AP-8-013 showed exquisite selectivity for Mpro with no inhibition at key mammalian cysteine proteases, cathepsin B and L, or the serine protease thrombin, while Cpd 22 (Cat B IC50 = 24 ± 7.5 nM, Cat L IC50 = 1.8 ± 0.3 nM) or GC-376 (Cat B IC50 = 37 ± 1.5 nM, Cat L IC50 = < 1 nM) showed poor selectivity towards mammalian cysteine proteases. AP-8-013 was active in CPE cell-based assays with comparable potency to reference compounds, with EC50 = 4.7 μM compared to Cmp 22 (EC50 = 1.4 μM) or GC-376 (EC50 = 1.1 μM). Using intact SARS-CoV-2 infection-based assays, AP-8-013 significantly inhibited parental virus as well as beta and delta VOC (EC50s = 2.7, 2.5, and 6.0 μM, respectively). Finally, a 31 molar mixture of AP-8-013 and remdesivir significantly enhanced antiviral activity in CPE assays (EC50 = 1.3 μM;p < 0.05) when compared against either compound alone (EC50s = 4.7 and 3.3 μM, respectively).

Conclusion:

We have identified a novel drug-like Mpro inhibitor lead series which is highly selective over cysteine and serine proteases that can inhibit multiple SARS-CoV-2 VOC and increase the antiviral activity of remdesivir.
Keywords
Search on Google
Collection: Databases of international organizations Database: EMBASE Language: English Journal: Topics in Antiviral Medicine Year: 2022 Document Type: Article

Similar

MEDLINE

...
LILACS

LIS

Search on Google
Collection: Databases of international organizations Database: EMBASE Language: English Journal: Topics in Antiviral Medicine Year: 2022 Document Type: Article