Compound repurposing
is an important strategy for the identification
of effective treatment options against SARS-CoV-2 infection and COVID-19
disease. In this regard, SARS-CoV-2 main protease (3CL-Pro), also
termed M-Pro, is an attractive drug target as it plays a central role
in viral replication by processing the viral polyproteins pp1a and
pp1ab at multiple distinct cleavage sites. We here report the results
of a repurposing program involving 8.7 K compounds containing marketed
drugs, clinical and preclinical candidates, and small molecules regarded
as safe in humans. We confirmed previously reported inhibitors of
3CL-Pro and have identified 62 additional compounds with IC50 values below 1 μM and profiled their selectivity toward chymotrypsin
and 3CL-Pro from the Middle East respiratory syndrome virus. A subset
of eight inhibitors showed anticytopathic effect in a Vero-E6 cell
line, and the compounds thioguanosine and MG-132 were analyzed for
their predicted binding characteristics to SARS-CoV-2 3CL-Pro. The
X-ray crystal structure of the complex of myricetin and SARS-Cov-2
3CL-Pro was solved at a resolution of 1.77 Å, showing that myricetin
is covalently bound to the catalytic Cys145 and therefore inhibiting
its enzymatic activity.
During the retrotranscription process, characteristic of all retroviruses, the viral ssRNA genome is converted into integration-competent dsDNA. This process is accomplished by the virus-coded reverse transcriptase (RT) protein, which is a primary target in the current treatments for HIV-1 infection. In particular, in the approved therapeutic regimens two classes of drugs target RT, namely, nucleoside RT inhibitors (NRTIs) and nonnucleoside RT inhibitors (NNRTIs). Both classes inhibit the RT-associated polymerase activity: the NRTIs compete with the natural dNTP substrate and act as chain terminators, while the NNRTIs bind to an allosteric pocket and inhibit polymerization noncompetitively. In addition to these two classes, other RT inhibitors (RTIs) that target RT by distinct mechanisms have been identified and are currently under development. These include translocation-defective RTIs, delayed chain terminators RTIs, lethal mutagenesis RTIs, dinucleotide tetraphosphates, nucleotide-competing RTIs, pyrophosphate analogs, RT-associated RNase H function inhibitors, and dual activities inhibitors. This paper describes the HIV-1 RT function and molecular structure, illustrates the currently approved RTIs, and focuses on the mechanisms of action of the newer classes of RTIs.
Overall, we provide the first demonstration that RNase H inhibition by DKAs is due not only to their chelating properties but also to specific interactions with highly conserved amino acid residues in the RNase H domain, leading to effective targeting of HIV retrotranscription in cells and hence offering important insights for the rational design of RNase H inhibitors.
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.