The SARS-CoV-2 coronavirus encodes an essential papain-like protease domain as part of its non-structural protein (nsp)-3, namely SARS2 PLpro, that cleaves the viral polyprotein, but also removes ubiquitin-like ISG15 protein modifications as well as, with lower activity, Lys48-linked polyubiquitin. Structures of PLpro bound to ubiquitin and ISG15 reveal that the S1 ubiquitin-binding site is responsible for high ISG15 activity, while the S2 binding site provides Lys48 chain specificity and cleavage efficiency. To identify PLpro inhibitors in a repurposing approach, screening of 3,727 unique approved drugs and clinical compounds against SARS2 PLpro identified no compounds that inhibited PLpro consistently or that could be validated in counterscreens. More promisingly, noncovalent small molecule SARS PLpro inhibitors also target SARS2 PLpro, prevent self-processing of nsp3 in cells and display high potency and excellent antiviral activity in a SARS-CoV-2 infection model.
Synthesis of the complexes (n-C6H5)Ru(L),CI [L = PPh,, PPh,Me, P(OMe),, AsPh,] and the related osmium compound (n-C6H5)0s(PPh3),Br are described. Reactions of (w-C5H6)Ru( PPh3),CI of three types were investigated: (a) replacement of the CI atom by, e.g. H, Me, C6Fs, or SnCI, groups; ( b ) replacement of one of the phosphine ligands by,e.g. CO, PPh,Me; (c) formation of cationiccomplexes of the type [(w-CsH6) Ru(PPh,),L] +, e.g. L = CO, MeCN. Twounusual complexes, (n-C5H6)Ru(PPh,)2BH,, and the hexachlorodizincate, [(r-C,H,) -Ru(PPh,),(MeCN)],Zn,CI,.are also reported.STUDIES l y 2 on ruthenium complexes containing both x-cyclopentadienyl and carbonyl ligands have shown that there is surprisingly little difference in reactivity between these complexes and the analogous ironcontaining compounds. However, the increased reactivity towards small molecules of phosphine complexes compared with carbonyl, together with the usefulness of some ruthenium@) complexes in many catalytic reaction^,^ suggested that a study of the chemistry of complexes of the type (x-C,H,)Ru(PR,),X would be worthwhile.Although (x-C,H,)Ru(CO),Cl can be readily obtained it is unlikely to be a useful precursor for compounds of the type (x-C5H5)Ru(PR3),X in view of work with the iron compounds (x-C,H,)Fe( CO),X which has shown that monodentate phosphines react to give only monocarbonyl complexes (x-C,H,)Fe(CO) (PR3)X.4* Only with triphenyl phosphite under forcing conditions have any fully substituted complexes of the type (x-C,H,)-Fe[P(OPh),],X been obtained.' Moreover, it has re-
The COVID-19 pandemic continues unabated, emphasizing the need for additional antiviral treatment options to prevent hospitalization and death of patients infected with SARS-CoV-2. The papain-like protease (PLpro) domain is part of the SARS-CoV-2 non-structural protein (nsp)-3, and represents an essential protease and validated drug target for preventing viral replication. PLpro moonlights as a deubiquitinating (DUB) and deISGylating enzyme, enabling adaptation of a DUB high throughput (HTS) screen to identify PLpro inhibitors. Drug repurposing has been a major focus through the COVID-19 pandemic as it may provide a fast and efficient route for identifying clinic-ready, safe-in-human antivirals. We here report our effort to identify PLpro inhibitors by screening the ReFRAME library of 11,804 compounds, showing that none inhibit PLpro with any reasonable activity or specificity to justify further progression towards the clinic. We also report our latest efforts to improve piperidine-scaffold inhibitors, 5c and 3k, originally developed for SARS-CoV PLpro. We report molecular details of binding and selectivity, as well as in vitro absorption, distribution, metabolism and excretion (ADME) studies of this scaffold. A co-crystal structure of SARS-CoV-2 PLpro bound to inhibitor 3k guides medicinal chemistry efforts to improve binding and ADME characteristics. We arrive at compounds with improved and favorable solubility and stability characteristics that are tested for inhibiting viral replication. Whilst still requiring significant improvement, our optimized small molecule inhibitors of PLpro display decent antiviral activity in an in vitro SARS-CoV-2 infection model, justifying further optimization.
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