Discovery of orally bioavailable SARS-CoV-2 papain-like protease inhibitor as a potential treatment for COVID-19.

The RNA-dependent RNA polymerase (RdRp), 3C-like protease (3CLpro), and papain-like protease (PLpro) are pivotal components in the viral life cycle of SARS-CoV-2, presenting as promising therapeutic targets. Currently, all FDA-approved antiviral drugs against SARS-CoV-2 are RdRp or 3CLpro inhibitors. However, the mutations causing drug resistance have been observed in RdRp and 3CLpro from SARS-CoV-2, which makes it necessary to develop antivirals with novel mechanisms. Through the application of a structure-based drug design (SBDD) approach, we discover a series of novel potent non-covalent PLpro inhibitors with remarkable in vitro potency and in vivo PK properties. The co-crystal structures of PLpro with lead compounds reveal that the residues D164 and Q269 around the S2 site are critical for improving the inhibitor's potency. The lead compound GZNL-P36 not only inhibits SARS-CoV-2 and its variants at the cellular level with EC50 ranging from 58.2 nM to 306.2 nM, but also inhibits HCoV-NL63 and HCoV-229E with EC50 of 81.6 nM and 2.66 μM, respectively. Oral administration of the GZNL-P36 results in significantly improved survival and notable reductions in lung viral loads and lesions in SARS-CoV-2 infection mouse model, consistent with RNA-seq data analysis. Our results indicate that PLpro inhibitors represent a promising SARS-CoV-2 therapy.

Lu Y ，Yang Q ，Ran T ，Zhang G ，Li W ，Zhou P ，Tang J ，Dai M ，Zhong J ，Chen H ，He P ，Zhou A ，Xue B ，Chen J ，Zhang J ，Yang S ，Wu K ，Wu X ，Tang M ，Zhang WK ，Guo D ，Chen X ，Chen H ，Shang J ... -  《Nature Communications》

Structure-Based Identification of Naphthoquinones and Derivatives as Novel Inhibitors of Main Protease M(pro) and Papain-like Protease PL(pro) of SARS-CoV-2.

Santos LH ，Kronenberger T ，Almeida RG ，Silva EB ，Rocha REO ，Oliveira JC ，Barreto LV ，Skinner D ，Fajtová P ，Giardini MA ，Woodworth B ，Bardine C ，Lourenço AL ，Craik CS ，Poso A ，Podust LM ，McKerrow JH ，Siqueira-Neto JL ，O'Donoghue AJ ，da Silva Júnior EN ，Ferreira RS ... -  《-》

Biological characterization of AB-343, a novel and potent SARS-CoV-2 M(pro) inhibitor with pan-coronavirus activity.

Since the SARS-CoV-2 outbreak, there have been ongoing efforts to identify antiviral molecules with broad coronavirus activity to combat COVID-19. SARS-CoV-2's main protease (Mpro) is responsible for processing the viral polypeptide into non-structural proteins essential for replication. Here, we present the biological characterization of AB-343, a covalent small-molecule inhibitor of SARS-CoV-2 Mpro with potent activity in both cell-based (EC50 = 0.018 μM) and enzymatic (Ki = 0.0028 μM) assays. AB-343 also demonstrated excellent inhibition of Mpro of other human coronaviruses, including those from the alpha (229E and NL63) and beta (SARS-CoV, MERS, OC43, and HKU1) families, suggesting the compound could be active against future coronaviruses. No change in AB-343 potency was observed against Mpro of SARS-CoV-2 variants of concern, including Omicron, suggesting that AB-343 could be developed as a treatment against currently circulating coronaviruses. AB-343 also remained active against several Mpro variants which confer significant resistance to nirmatrelvir and ensitrelvir, which are presently the only Mpro inhibitors authorized for the treatment of COVID-19, further supporting the evaluation of AB-343 as a novel and potent therapeutic for COVID-19 and other coronaviruses.

McGovern-Gooch KR ，Mani N ，Gotchev D ，Ardzinski A ，Kowalski R ，Sheraz M ，Micolochick Steuer HM ，Tercero B ，Wang X ，Wasserman A ，Chen CY ，von König K ，Maskos K ，Prasad A ，Blaesse M ，Bergmann A ，Konz Makino DL ，Fan KY ，Kultgen SG ，Lindstrom A ，Nguyen D ，Vega M ，Wang X ，Bracci N ，Weiss SR ，Cole AG ，Lam AM ，Cuconati A ，Sofia MJ ... -  《-》

Dual Inhibitors of SARS-CoV-2 3CL Protease and Human Cathepsin L Containing Glutamine Isosteres Are Anti-CoV-2 Agents.

Kumar V ，Zhu J ，Chenna BC ，Hoffpauir ZA ，Rademacher A ，Rogers AM ，Tseng CT ，Drelich A ，Farzandh S ，Lamb AL ，Meek TD ... -  《-》

Repurposing FDA-approved drugs for COVID-19: targeting the main protease through multi-phase in silico approach.

Metwaly AM ，Elkaeed EB ，Alsfouk AA ，Ibrahim IM ，Elkady H ，Eissa IH ... -  《-》