Recently, a cocktail of REGN10987 and REGN10933 antibodies was shown to be an excellent candidate for the treatment of Covid-19. simulations are in good agreement with the experimental data. Thus, REGN10933 is probably a better candidate for treating Covid-19 than REGN10987, although the cocktail appears to neutralize the virus more efficiently than REGN10933 or REGN10987 alone. The association of REGN10987 with RBD is driven by van der Waals interactions, while electrostatic interactions dominate in the case of REGN10933 and the cocktail. We also studied the effectiveness of these antibodies on the two most dangerous variants Delta and Omicron. Consistent with recent experimental reports, our results confirmed that the Omicron variant reduces the neutralizing activity of REGN10933, REGN10987, and REGN10933+REGN10987 with the K417N, N440K, L484A, and Q498R mutations playing a decisive role, while the Delta variant slightly changes their activity. 1.?Introduction Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a member of the Coronaviridae family and the causative agent of the ongoing coronavirus disease 2019 (Covid-19) pandemic.1 Currently, over 245 million cases have been officially diagnosed since its first emergence, and more than 5 million people have died from Covid-19.2 Public health measures, along with rapid vaccine development, have helped slow the pandemic in some countries. Moreover, small-molecule inhibitors, antibody-based therapeutics, and convalescent plasma from recovered Covid-19 patients have received emergency use approvals.3 Monoclonal antibody (mAb) therapies for the treatment of SARS-CoV-2 have proven to be an excellent solution to reduce virus loads and alleviate symptoms when given shortly after diagnosis.4,5 mAbs bind to the virus through the spike protein Rabbit Polyclonal to RAB3IP (S), which consists of the S1 and S2 subunits (Figure ?Figure11A), blocking the binding of SARS-CoV-2 to human angiotensin-converting enzyme 2 (ACE2) (Figure ?Figure11B), in turn preventing infection.6 mAbs often target the S1 subunit,7 which contains the receptor-binding domain (RBD) and N-terminal domain (NTD). RBD-specific mAbs fall into four main classes, while NTD-specific mAbs target the patch remote from RBD.8,9 The discovery of mAbs that target S2 is another area of active research.8 Open in a separate window Figure 1 (A) Schematic description of the S protein of SARS-CoV-2, which consists of S1 and S2 subunits. (B) REGN10933 and REGN10987 bind to S protein, preventing the virus from entering cells. (C) Three-dimensional (3D) structures of REGN10933 and REGN10987 bound to RBD are shown in all-atom representation. Antibody cocktails, defined as mixtures of more than one unique antibody, have shown promise in preventing viruses from escaping neutralization studies showed that combining two noncompeting antibodies protects against the rapid escape seen with individual antibody components.13 This combination-based approach has been supported by subsequent studies showing that REGN-COV2 retains neutralization potency against SARS-CoV-2.12,13 Table 1 is the force constant, is the pulling velocity at time is JD-5037 the displacement of the chains atom connected to the spring in the direction of pulling, respectively. The spring constant value was set to 600 kJ/(mol nm2) (1020 pN/nm), which is a typical value used in atomic force microscopy (AFM) experiments.37 The complete dissociation of REGN10933 or REGN10987 or RBD from the binding region was reached during simulations of duration 10,000 ps at pulling speed = 0.5 nm/ns. Open in a separate window Figure 2 Structure of the REGN10933+REGN10987-RBD complex, retrieved from JD-5037 PDB with ID 6XDG. RBD is shown in orange, while green and blue describe REGN10987 and REGN10933. The external force is applied to (A) REGN10933, (B) REGN10987, and (C) RBD (REGN10933+REGN10987). The pulling direction in SMD simulations JD-5037 is shown with a spring along the is the number of simulation steps, and and are the force experienced by the target and position at step was defined by39 3 here, ?…?is the average over trajectories, is the time-dependent displacement, and defined as eq 2. Equation 3 means that we can extract an equilibrium quantity by assembling the external work of an infinite number of nonequilibrium processes.40 In this JD-5037 study, while the transformation is not slow enough and the number of SMD runs is finite, we are able to estimate the nonequilibrium binding and unbinding energy barriers of the complexes based on the transition state (TS), the bound state.
Recently, a cocktail of REGN10987 and REGN10933 antibodies was shown to be an excellent candidate for the treatment of Covid-19