Main protease mutants of SARS-CoV-2 variants remain susceptible to PF-07321332
Ullrich et al.,
Main protease mutants of SARS-CoV-2 variants remain susceptible to PF-07321332,
bioRxiv, doi:10.1101/2021.11.28.4702264 (Preprint) (In Vitro)
In Vitro study showing that PF-07321332 maintains efficacy against variants C.37 lambda, B.1.1.318, B.1.2, B.1.351 beta, and P.2 zeta.
Ullrich et al., 30 Nov 2021, preprint, 4 authors.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
Abstract: bioRxiv preprint doi: https://doi.org/10.1101/2021.11.28.470226; this version posted November 30, 2021. The copyright holder for this
preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in
perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license.
Main protease mutants of SARS-CoV-2 variants remain susceptible to PF-07321332
Sven Ullrich, Kasuni B. Ekanayake, Gottfried Otting, Christoph Nitsche*
Research School of Chemistry, Australian National University, Canberra, ACT 2601, Australia
*christoph.nitsche@anu.edu.au
Graphical Abstract
Keywords
SARS-CoV-2, main protease, variants, PF-07321332, inhibitors
Abstract
The COVID-19 pandemic continues to be a public health threat. Multiple mutations in the spike
protein of emerging variants of SARS-CoV-2 appear to impact on the effectiveness of available
vaccines. Specific antiviral agents are keenly anticipated but their efficacy may also be
compromised in emerging variants. One of the most attractive coronaviral drug targets is the
main protease (Mpro). A promising Mpro inhibitor of clinical relevance is the peptidomimetic
PF-07321332. We expressed Mpro of five SARS-CoV-2 lineages (C.37 Lambda, B.1.1.318,
B.1.2, B.1.351 Beta, P.2 Zeta), each of which carries a strongly prevalent missense mutation
(G15S, T21I, L89F, K90R, L205V). Enzyme kinetics showed that these Mpro variants are
similarly catalytically competent as the wildtype. We show that PF-07321332 has similar
potency against the variants as against the wildtype. Our in vitro data suggest that the efficacy
of specific Mpro inhibitors such as PF-07321332 is not compromised in current COVID-19
variants.
1
bioRxiv preprint doi: https://doi.org/10.1101/2021.11.28.470226; this version posted November 30, 2021. The copyright holder for this
preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in
perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license.
Since its emergence in late 2019,1 COVID-19 has significantly impacted on societies
worldwide.2 More than 5 million deaths have been attributed to COVID-19, with the number
of confirmed SARS-CoV-2 infections surpassing 250 million.3 The outbreak of SARS-CoV-2
prompted multiple successful vaccine development campaigns.4 Currently approved vaccines,
such as viral vector or mRNA vaccines, successfully limited the pandemic’s impact on global
health.5, 6 Most COVID-19 vaccines function by stimulating an immune response against the
SARS-CoV-2 spike protein (S)7-9 but, as the spike gene has gathered pronounced genetic
variability,10, 11 it is a common concern that the effectiveness of existing vaccines may be
affected by those variants of SARS-CoV-2.5, 6, 10, 12 At the time of writing, the World Health
Organization (WHO) lists four variants of concern (VOC; Alpha, Beta, Gamma, Delta) and
two variants of interest (VOI; Lambda, Mu).13 A possible adjustment of the vaccines to
currently circulating lineages of SARS-CoV-2 is being investigated.14-16 It is clear that the
deployment of vaccines remains the best public health measure to control the spread of SARSCoV-2 and the severe health effects of COVID-19.17, 18
Complementary to preventive vaccines, antiviral drugs are urgently needed to combat
COVID-19.19 Since the discovery of SARS-CoV-1 in 2003,20 several coronaviral drug targets
have been identified,21..
Please send us corrections, updates, or comments. Vaccines and
treatments are complementary. All practical, effective, and safe means should
be used based on risk/benefit analysis. No treatment, vaccine, or intervention
is 100% available and effective for all current and future variants. We do not
provide medical advice. Before taking any medication, consult a qualified
physician who can provide personalized advice and details of risks and
benefits based on your medical history and situation.
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provide treatment protocols.
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