Recent Advances in SARS-CoV-2 Main Protease Inhibitors: From Nirmatrelvir to Future Perspectives

Abstract

The main protease (Mpro) plays a pivotal role in the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is considered a highly conserved viral target. Disruption of the catalytic activity of Mpro produces a detrimental effect on the course of the infection, making this target one of the most attractive for the treatment of COVID-19. The current success of the SARS-CoV-2 Mpro inhibitor Nirmatrelvir, the first oral drug for the treatment of severe forms of COVID-19, has further focused the attention of researchers on this important viral target, making the search for new Mpro inhibitors a thriving and exciting field for the development of antiviral drugs active against SARS-CoV-2 and related coronaviruses.

Design, Synthesis, and Biological Evaluation of Trisubstituted Piperazine Derivatives as Noncovalent Severe Acute Respiratory Syndrome Coronavirus 2 Main Protease Inhibitors with Improved Antiviral Activity and Favorable Druggability

“…Yet it was not quite active in cellular antivirus experiments, presumably due to its limited permeability. Enzyme inhibitory activities were basically lost (<10% inhibition at 10 μM) when azoles, fused heterocycles ( GC-54 , GC-62 , GC-63 , GC-64 , GC-73 , and GC-76 ), or various lactam rings ( GC-57 , GC-58, and GC-59 ) were introduced, although these constitute common privileged fragments in peptide-like M pro inhibitors. ,, …”

“…were determined on a micro melting point apparatus (RY-1G, Tianjin TianGuang Optical Instruments). 1 H NMR and 13 C NMR spectra were recorded in DMSO-d 6 on a Bruker AV-600 spectrometer, with tetramethyl silane (TMS) as the internal standard. Coupling constants were given in hertz, and chemical shifts were reported in δ values (ppm) from TMS.…”

“…White foam solid, 43% yield, melting point 83−85 °C. 1 (13). To a solution of compound 9 (5.0 g, 12.89 mmol) in DCM (70 mL) was added TFA (7.35g, 64.5 mmol) dropwise.…”

“…Most of them are peptide-like covalent inhibitors, such as Nirmatrelvir ( 1 , PF-07321332), Simnotrelvir ( 2 , SIM0417), and Leritrelvir ( 3 , RAY1216), which have been launched in different countries (Figure ). However, most peptide-like inhibitors have obvious drawbacks, e.g., low membrane permeability and metabolic stability, and Ritonavir must be used as a pharmacokinetic enhancer in some cases, potentially leading to drug–drug interactions. , In addition, the peptide-like covalent inhibitors FB2001­( 4 ), MI-30 ( 5 ), and PF-00835231­( 6 ), possessing similar structures, are currently evaluated in clinical trials. In the past years, several SARS-CoV-2 strains with M pro mutations have been discovered among naturally occurring viruses that are resistant against Nirmatrelvir. − Hence, it is necessary to develop a new generation of M pro inhibitors to fight SARS-CoV-2 infections.…”

“…However, most peptide-like inhibitors have obvious drawbacks, e.g., low membrane permeability and metabolic stability, and Ritonavir must be used as a pharmacokinetic enhancer in some cases, potentially leading to drug−drug interactions. 12,13 In addition, the peptide-like covalent inhibitors FB2001(4), 14 MI-30 (5), 15 and PF-00835231(6), 16 possessing similar structures, are currently evaluated in clinical trials. In the past years, several SARS-CoV-2 strains with M pro mutations have been discovered among naturally occurring viruses that are resistant against Nirmatrelvir.…”