# Discovery of Spiro[chromane-2,4′-piperidine] Derivatives as Irreversible Inhibitors of SARS-CoV‑2 Papain-like Protease

## TL;DR

Researchers discovered a new class of compounds that strongly inhibit a key enzyme in SARS-CoV-2, offering potential for antiviral treatments.

## Contribution

A novel class of spiro[chromane-2,4′-piperidine] derivatives was developed as irreversible inhibitors of SARS-CoV-2 PLPro.

## Key findings

- Lead compound 45 inhibited PLPro with an IC50 of 0.059 μM.
- Compound 45 showed antiviral activity in A549 cells with an EC50 of 2.1 μM.
- The inhibitors could help combat drug-resistant viral strains and future coronavirus outbreaks.

## Abstract

The papain-like protease (PLPro) plays a key
role in
SARS-CoV-2 replication and represents a promising target for the development
of new antiviral therapies. Previous efforts to develop fragment-derived
inhibitors of PLPro led to the identification of a novel
class of spiro­[chromane-2,4′-piperidin]-4-one inhibitors exemplified
by lead compound 7. High-resolution covalent cocrystal
structures and molecular dynamics simulations were utilized to guide
the development of a series of low-nanomolar irreversible PLPro inhibitors, with lead compound 45 demonstrating strong
enzymatic inhibition (IC50 = 0.059 μM at T = 60 min) and antiviral activity in A549 cells (EC50 = 2.1 μM at 48 hpi). This novel class of inhibitors
represents a promising avenue for the development of therapeutics
to overcome the potential of drug-resistant viral strains and future
coronavirus outbreaks.