SARS-CoV-2 is a severe and often lethal disease that belongs to the genus Betacoronavirus. SARS-CoV-2 releases non-structural proteins (NSPs), which function within cell walls, they work to deteriorate the cell, make the cell easier to infect and replicate viral RNA. NSP3 or papain-like protease (PLpro) is a cysteine protease which cleaves NSPs 1-3. PLpro aids in viral proliferation and counteracts the host immune response, thus inhibition of PLpro could greatly reduce the infectivity of SARS-CoV-2. Additionally, PROTACs are heterobifunctional molecules, which degrade a protein via the proteasome degradation pathway. We aim to develop and biochemically test a range of PLpro binding PROTACs by performing coupling reactions, which link an E3 ligase binder to solvent-accessible functional groups on the previous inhibitor XR8-24. Further, computer-aided drug-design (CADD) may beneficially impact PROTAC development. We plan to use PROTAC conformational sampling and PROTAC MD to determine the optimal E3 ligase, estimate optimal linker length and assess ternary complex stability. Thus far, we have synthesised PLpro inhibitor XR8-24, optimised Shen et. al.’s reported reaction conditions, synthesised an analogue (compound 8) and shown that several analogues can be made. Next, we will link these compounds to an E3 ligase binder. Additionally, we have performed MD simulations on PROTACs and shown that conformational sampling can approximate the ternary complex formed.