Structure genomics of SARS-CoV-2 and its Omicron variant: drug design templates for COVID-19

Abstract

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has brought an unprecedented public health crisis and persistently threatens to humanity. With tireless efforts from scientists around the world, understanding of the biology of coronavirus has been greatly enhanced over the past 2 years. Structural biology has demonstrated its powerful impact on uncovering structures and functions for the vast majority of SARS-CoV-2 proteins and guided the development of drugs and vaccines against COVID-19. In this review, we summarize current progress in the structural biology of SARS-CoV-2 and discuss important biological issues that remain to be addressed. We present the examples of structure-based design of Pfizer’s novel anti-SARS-CoV-2 drug PF-07321332 (Paxlovid), Merck’s nucleotide inhibitor molnupiravir (Lagevrio), and VV116, an oral drug candidate for COVID-19. These examples highlight the importance of structure in drug discovery to combat COVID-19. We also discussed the recent variants of Omicron and its implication in immunity escape from existing vaccines and antibody therapies.

Structural and biochemical mechanism for increased infectivity and immune evasion of Omicron BA.1 and BA.2 variants and their mouse origins

“…Within the S1 subunit is an N-terminal domain (NTD) of unknown function and a C-terminal receptor-binding domain (RBD). The S2 subunit contains a conserved fusion peptide (FP) motif that is mostly hydrophobic and capable of mediating viral fusion with host cells 7 . Extensive structures of the spike trimer reveal the open and closed conformations for the three RBD within the spike trimer, where the open “up” RBD conformation is prerequisite for ACE2 binding.…”

“…The trimeric spike protein is a major membrane surface glycoprotein of SARS-CoV-2 that mediates the binding to the host receptor ACE2 and subsequent viral entry into cells. [5][6][7] The matured spike protein contains two subunits: an ACE2 binding S1 subunit and a membrane-fusion S2 subunit. Within the S1 subunit is an N-terminal domain (NTD) of unknown function and a C-terminal receptor-binding domain (RBD).…”

“…The S2 subunit contains a conserved fusion peptide (FP) motif that is mostly hydrophobic and capable of mediating viral fusion with host cells. 7 Extensive structures of the spike trimer reveal the open and closed conformations for the three RBDs within the spike trimer, where the open "up" RBD conformation is prerequisite for ACE2 binding. 3,6,[8][9][10][11][12] Upon ACE2 binding, the spike trimer undergoes conformational changes to expose the FP motif of the S2 subunit to initiate membrane fusion that allows the release of the viral genome into host cells.…”

An exhaustive comprehension of the role of herbal medicines in Pre- and Post-COVID manifestations

“…Another Nsp3 protein responsible for CoV is RTC formation. It releases Nsp1, Nsp2, and interacts with other Nsps and RNA to form RTC ( Hardenbrook and Zhang, 2022 ; Wu et al, 2022 ).…”

COVID-19 inflammation and implications in drug delivery

“…COVID-19 infection is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a single positive-strand RNA virus belonging to β coronaviruses. The pathogenesis of the virus is mainly mediated by its envelope (E), membrane (M) and nucleocapsid (N) structural proteins, as well as its spike (S) glycoprotein facilitating its cell entry through the binding to angiotensin-converting enzyme-2 (ACE2) receptors highly expressed on pulmonary epithelial cells [ [1] , [2] , [3] , [4] ]. Although the pathogenesis of this disease is still not completely understood, growing evidence indicates that a dysregulated inflammatory syndrome is narrowly associated with COVID-19 severity and poor prognosis [ [5] , [6] , [7] , [8] ].…”