Aptamer BC 007 - Efficient binder of spreading-crucial SARS-CoV-2 proteins

Abstract

Corona virus disease 2019 (COVID-19) is a respiratory disease caused by a new coronavirus (SARS-CoV-2) which causes significant morbidity and mortality. The emergence of this novel and highly pathogenic SARS-CoV-2 and its rapid international spread poses a serious global public health emergency. To date 32,174,627 cases, of which 962,613 (2.99%) have died, have been reported ( https://www.who.int/westernpacific/health-topics/coronavirus , accessed 23 Sep 2020). The outbreak was declared a Public Health Emergency of International Concern on 30 January 2020. There are still not many SARS-CoV-2-specific and effective treatments or vaccines available. A second round of infection is obviously unavoidable. Aptamers had already been at the centre of interest in the fight against viruses before now. The selection and development of a new aptamer is, however, a time-consuming process. We therefore checked whether a clinically developed aptamer, BC 007, which is currently in phase 2 of clinical testing for a different indication, would also be able to efficiently bind DNA-susceptible peptide structures from SARS-CoV-2-spreading crucial proteins, such as the receptor binding domain (RBD) of the spike protein and the RNA dependent RNA polymerase of SARS-CoV-2 (re-purposing). Indeed, several such sequence-sections have been identified. In particular for two of these sequences, BC 007 showed specific binding in a therapy-relevant concentration range, as shown in Nuclear magnetic resonance (NMR)- and Circular dicroism (CD)-spectroscopy and isothermal titration calorimetry (ITC). The excellent clinical toxicity and tolerability profile of this substance opens up an opportunity for rapid clinical testing of its COVID-19 effectiveness.

Heparin: A simplistic repurposing to prevent SARS-CoV-2 transmission in light of its in-vitro nanomolar efficacy

“…The purple surface model of Chain B represents a closed state in which RBD is facing inwards and seems to be inactive for ACE2 binding. The processing sites are described according to earlier reports [ 74 ]. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)…”

Aptamer BC 007’s Affinity to Specific and Less-Specific Anti-SARS-CoV-2 Neutralizing Antibodies

“…These are all different specific characteristics that make these three mABs valuable candidates for an investigation of their potential interactions with BC 007, given the publicly available sequences of the CDR-H3 and L3 regions of all of their investigated clones and the entire heavy- and light-chain sequences for CV07-250 and CV07-270 (PDB IDs 6XKQ and 6XKP, respectively) [ 21 ]. We checked those sequences for theoretical susceptibility and accessibility to interact with DNA according to previous work [ 1 ].…”

“…NMR measurements were carried out as recently described by Weisshoff et al while investigating the interaction of BC 007 with sequence sections of growth-essential SARS-CoV-2 proteins [ 1 ]. While investigating the interaction of BC 007 with sequence sections of anti-SARS-CoV-2 mABs, all NMR measurements were carried out on a Bruker AV600 spectrometer (Bruker Biospin, Rheinstetten, Germany) at 600 MHz in 90/10 H 2 O/D 2 O at 298 K. The final concentration of BC 007 and the peptides (ARDGVIPPRFDY, ARARGSSGWYRIGTRWGNWFDP, AGSDNYGFPYNGMDV) was 1 mM.…”

“…In an initial screening experiment, a solution of 4 mM peptide was titrated in 2 µL steps into the 200 µM BC 007 solution in the calorimeter cell, in order to be comparable to results published by Weisshoff et al [1]. The generated data were used to adjust the necessary concentration range to allow for precise measurements, which amounted to 12 mM peptide in the syringe and 600 µM BC 007 in the measuring cell.…”

“…Aptamer BC 007, currently under development for the neutralization of functionally active autoantibodies in autoantibody-associated heart failure, was recently reported to be a specific binder of DNA-binding-susceptible sequence sections of proteins crucial for the growth of SARS-CoV-2, such as the spike protein and the RNA-dependent RNA polymerase [ 1 ]. This would provide the opportunity to quickly check for in vivo efficiency in COVID-19 patients given the advanced state of this drug’s development.…”