Week of 20 March to 27 March, 2020
Results from a Chinese open-label trial with two protease inhibitors developed for HIV treatment, lopinavir and ritonavir, were disappointing, as reported by Cao et al. in the New England Journal of Medicine. The study did not show clinical benefits or viral-load reduction in a population of 199 patients infected with SARS-CoV-2. A smaller randomized clinical trial by Li et al., published as a preprint in MedRxiv, compared lopinavir–ritonavir to the influenza drug umifenovir and also did not detect any clinical improvement in the protease-inhibitor-treated group. Nonetheless, the combination features prominently in the large-scale SOLIDARITY trial launched by the World Health Organization (WHO), both alone and in combination with interferon-β. The other two treatments included in the WHO trials are the RNA-dependent RNA-polymerase inhibitor remdesivir from Gilead Sciences and the anti-malarial agents chloroquine and hydroxychloroquine.
As policymakers and public-health officials struggle with the implications of competing epidemiological models, identifying previously exposed and asymptomatic carriers of SARS-CoV-2 is critical. Studies led by Florian Krammer (Icahn School of Medicine at Mount Sinai, New York) and Bart Haagmans (Erasmus Medical Center, Rotterdam) tackle this problem by developing specific serological tests that are compatible with standard ELISA kits and detect antibodies to cloned SARS-CoV-2 spike protein, its receptor-binding domain and (in the latter study) the nucleocapsid protein.
A multicenter collaborative effort has generated an extensive target list for pharmacological repurposing trials, which should keep researchers busy for some time. Using 26 cloned viral proteins as bait in an affinity purification mass spectrometry screen, the authors fished out 332 interacting human proteins, thus leading to the identification of 69 different US Food and Drug Administration–approved drugs that could potentially disrupt the virus–host interactome. In addition to the expected hits in antiviral immunity pathways, a wide range of cellular processes are implicated, including transcription, translation, trafficking and protein turnover. This plethora of promising compounds will require extensive in vivo validation. Ralph Baric and colleagues focused on β-d-N4-hydroxycytidine (NHC), a ribonucleoside analog previously shown to have antiviral effects against a broad range of RNA viruses. NHC decreased the in vitro replication of MERS-CoV, SARS-CoV and SARS-CoV-2, and was protective in vivo in a mouse model of SARS-CoV infection. Importantly, the study also suggests that remdesivir-resistant mutants may have enhanced sensitivity to NHC.
Viral origin and structure
Comparative genome studies published in Nature Medicine and Current Biology strongly support that SARS-CoV-2 originated in bats and that pangolins (Manis javanica) were an intermediate mammalian host. Zhang et al. (Current Biology) identify a closely related virus in lung samples from two Malayan pangolins. Pangolin-CoV and SARS-CoV-2 share five key amino acid substitutions in the receptor-binding domain, in residues potentially affecting the domain’s affinity for ACE2. Furthermore, in Cell, Wang et al. solve the crystal structure of the SARS-CoV-2 spike-protein C-terminal domain in complex with human ACE2. A comparison to previously published data for SARS-CoV binding the ACE2 suggests that the SARS-CoV2 spike C-terminal domain has much stronger affinity for ACE2, with more atomic points of contact.