In light of the current outbreak of a novel coronavirus (2019-nCoV) in China, ACS Publications is releasing a free-to-read Virtual Issue, featuring a collection of articles on coronavirus research.
Note: On February 11, 2020, the World Health Organization announced the official name for the disease caused by the coronavirus is COVID-19.
Coronaviruses represent a large family of viruses that elicit respiratory illness in humans, including the common cold and more serious diseases, such as Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS). This group of viruses can also infect animals and are zoonotic, meaning they can be transmitted between animals and humans, as was shown to be the case for MERS and SARS. In fact, some species of animals, such as bats, act as reservoirs for carrying wide varieties of viruses, and severe viral outbreaks in the human population such as for SARS and MERS tend to occur when these viruses jump from animals to humans when given the opportunity due to close interaction. The novel coronavirus (currently referred to as 2019-nCoV) was first detected in Wuhan, China, in December 2019 and appeared to initially affect people who had visited a seafood and animal market selling live game, but person-to-person spreading occurred as well. Investigations on the source 2019-nCoV are actively ongoing, and knowledge of the virus, such as its transmissibility and incubation period, is constantly developing.
Chemistry has a key role to play in understanding everything from viral structure to pathogenesis, isolation of vaccines and therapies, as well as in the development of materials and techniques used by basic researchers, virologists, and clinicians. ACS Chemical Biology Editor-in-Chief, Laura Kiessling, notes that “Fundamental research to understand the molecules that govern virus structure and function can accelerate the discovery of means to treat and prevent infectious disease. Events such as the current novel coronavirus outbreak highlight the essentiality of basic research and the need for sustained research funding so that comprehensive resources exist when a rapid response is required.”
This Virtual Issue provides a brief overview of the important contributions of chemistry to understanding and controlling the spread of coronaviruses. ACS Infectious Diseases Associate Editor and virologist, Priscilla Yang, says “This Virtual Issue shines a light on various research efforts past & present to facilitate rapid development of diagnostics and therapeutics for coronavirus, and the important role that chemistry has to play in translational discovery.”
Basic Viral Structure and Mechanism of Infection
Scientists have moved rapidly to characterize 2019-nCoV and widely disseminate their findings amongst the international research community as quickly as possible. One important example of this is the homology models of the novel coronavirus cysteine protease produced by Stoermer. The rapid availability of nCoV genomic data made possible the production of first-generation homology models for 3CLpro cysteine protease; an enzyme which is crucial for viral replication and has been explored previously as a target for antiviral therapies in the treatment of another coronavirus, SARS. This preprint notes that though the viral genome bears a close similarity to bat coronaviruses, the protease exhibits the closest homology with SARS CoV protease a zoonotic virus that entered the human population via civets.
Huang et al. used crystallographic and biophysical methods to conduct structural and functional characterization of HKU9-RBD — a bat coronavirus that has not crossed over to humans. The rationale for these studies was that bat betacoronaviruses (a genus that includes SARS and MERS) should be well characterized in the event that they end up being the source of the next global pandemic. Upon comparison of the HKU9-RBD receptor-binding domain (RBD) to the available structures of the SARS-, MERS-, and HKU4- (another bat coronavirus) RBDs, the authors found that even though the evolutionary histories of RNA viruses tend to be difficult to determine due to substantial evolutionary pressure, the coronaviruses in this study exhibited several conserved tertiary structural features in the core subdomain of the spike (S) protein. This spike protein, present on the virion surface, is a key factor in determining the species tropism of the virus as it is involved in receptor recognition and membrane fusion as part of the mechanism of infection. The authors concluded that their findings supported the notion that the S protein of betaCoV divergently evolves from a common ancestor, particularly in the external RBD region, and that this determines the potential of a particular betaCoV virus for interspecies transmission.
Lee et al. conducted high-throughput screening of 25,000 compounds, seeking a small molecule dual inhibitor for the papain-like protease (PLpro) enzymes of MERS-CoV and SARS-CoV. The authors were able to identify a compound with inhibitory activity against both enzymes though interestingly, despite the fact that the two enzymes bear significant similarities in their overall structures and catalytic sites, the identified compound acts as a competitive inhibitor against MERS-CoV PLpro, and an allosteric inhibitor against SARS-CoV PLpro as determined using SPR. Further, though this suggests that the inhibitor recognition specificity of the compound may differ for MERS-CoV PLpro and SARS-CoV PLpro, the inhibitor was selective for both of these over two human homologs. Two residues identified through structure and sequence alignments, Y269 and Q270 of the SARS-CoV PLpro were replaced by T274 and A275 in MERS-CoV PLpro complicating the potential for critical binding interactions. Taking this into consideration along with the finding that none of the four tested SARS-CoV PLpro lead inhibitors were effective against MERS-CoV PLpro, it is notable that a dual functionality inhibitor was identified for both of the SARS and MERS papain-like proteases.
The development of therapeutics for known coronaviruses, as well as 2019-nCoV, is an active research area. A review by Morse et al. deposited on ChemRxiv discusses potential prevention and treatment options for 2019-nCoV. There are four crucial enzymes that are necessary for pathogenesis: the spike protein that facilitates virus entry through the host cell surface receptor angiotensin-converting enzyme 2, the coronavirus main protease 3CLpro and the papain-like protease PLpro that are involved in assembly of new virions, and the RNA-dependent RNA polymerase RdRp that facilitates replication of the CoV RNA genome. The authors argue that the differences between the SARS-CoV and 2019-nCoV spike protein will likely require the development of novel therapeutics. The PLpro enzymes from the two viruses only share 83% sequence identity but do not differ in their main secondary structure components that form the active site. Hence, inhibitors developed for the SARS-nCoV PLpro may also be active against the 2019-nCoV enzyme. The 2019-nCoV and SARS RdRp and 3CLpro share significant sequence identity and would make the application of previously developed small molecule therapeutics based on the SARS-CoV proteins feasible, such as remdesivir and 3LCpro-1.
A more general review by Falcinelli et al. presents the importance of integrating clinical and basic research for the investigation of viral pathogens and the development of novel therapeutics. A perspective by Pillaiyar et al. provides an overview of chemotherapies developed against the SARS protease SARS-CoV 3CLpro between 2003, when the SARS outbreak occurred, and 2015. Mehellou et al. review the ProTide technology in their miniperspective, an approach that facilitates intracellular delivery of nucleoside analog monophosphates and monophosphates. The ProTide GS-5734 developed by Gilead Sciences reportedly exhibited broad-spectrum antiviral activity against a number of viruses, including coronaviruses. In their viewpoint, Schor and Einav discuss the repurposing of existing drugs as broad-spectrum agents for the treatment of intracellular pathogens and point out that kinase inhibitors, such as imatinib and nilotinib inhibit coronaviruses such as SARS and MERS. An article published in Chemical & Engineering News reports on the mobilization efforts of drug companies and biotechnology firms to rapidly develop diagnostics and treatments for 2019-CoV
Original research articles featured in this Virtual Issue include the article by Wang et al. who disclose a strategy for preparing a vaccine against SARS-CoV that involved targeting a specific epitope of the virus spike protein. Yoon et al. report the synthesis of aristeromycin analogs as dual-target antiviral compounds capable of inhibiting the RdRp proteinase of various RNA viruses and the host cell S-adenosyl-L-homocysteine hydrolase. Two articles by Kei Liu and colleagues present viral fusion inhibitors against MERS-COV.
Kvach et al. report the development of the first substrate-like APOBEC3 inhibitors as a strategy for augmenting antiviral (and anticancer) therapies. APOBEC3, an enzyme that is a component of the innate immune system, mounts an effective defense against viral infection by altering pathogen-derived genetic material and thereby rendering it non-functional. Specifically, APOBEC3 converts 2’-deoxycytidines to 2’-deoxyuridines on single-stranded DNA via deamination. Viruses have of course evolved strategies to use this mutagenesis function of APOBEC3 to their advantage or to evade it altogether. The authors investigate ssDNA that include the cytidine nucleoside analog 2’-deoxyzebularine as substrate-like APOBEC3 inhibitors; the first such platform for this application.
Coronavirus Virtual Issue – Update 2/17
Exploiting the similarities in active site morphology of the main and 3C proteases of coronaviruses and enteroviruses, Zhang et al. pursued broad-spectrum antivirals by designing, synthesizing and characterizing peptidomimetic a-ketoamides inhibitors. Evaluation of lead compounds against the recombinant proteases, in viral replicons, and in virus-infected cells led to further optimization efforts culminating in the discovery of compound 11r that demonstrated potent anti-MERS-CoV activity in a human liver cell line. Due to the similarities exhibited by proteases of MERS-CoV and the novel coronavirus, the authors propose that compound 11r is likely also active against COVID-19.
Call for Coronavirus-Related Papers
ACS Publications is committed to rapidly communicating urgent developments in characterizing, preventing, and treating 2019-nCoV.
ACS Publications welcomes you to consider ACS journals for your coronavirus-related work and plans to expedite the review process. To learn more, visit: ACS Infectious Diseases, Journal of Medicinal Chemistry, ACS Medicinal Chemistry Letters, ACS Pharmacology & Translational Science, ACS Chemical Biology, and Biochemistry.
ACS also welcomes submissions to ChemRxiv, the preprint server for chemistry that is jointly maintained by the American Chemical Society, the Chinese Chemical Society, The Chemical Society of Japan, the German Chemical Society, and the Royal Society of Chemistry.
If you are unsure whether your manuscript is a good fit for your intended target journal, you may send a pre-submission inquiry to the journal’s Editorial Office.