COVID-19 update: The race to therapeutic development

Abstract

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), represents an unprecedented challenge to global public health. At the time of this review, COVID-19 has been diagnosed in over 40 million cases and associated with 1.1 million deaths worldwide. Current management strategies for COVID-19 are largely supportive, and while there are more than 2000 interventional clinical trials registered with the U.S. National Library of Medicine (clinicaltrials.gov), results that can clarify benefits and risks of candidate therapies are only gradually becoming available. We herein describe recent advances in understanding SARS-CoV-2 pathobiology and potential therapeutic targets that are involved in viral entry into host cells, viral spread in the body, and the subsequent COVID-19 progression. We highlight two major lines of therapeutic strategies for COVID-19 treatment: 1) repurposing the existing drugs for use in COVID-19 patients, such as antiviral medications (e.g., remdesivir) and immunomodulators (e.g., dexamethasone) which were previously approved for other disease conditions, and 2) novel biological products that are designed to target specific molecules that are involved in SARS-CoV-2 viral entry, including neutralizing antibodies against the spike protein of SARS-CoV-2, such as REGN-COV2 (an antibody cocktail), as well as recombinant human soluble ACE2 protein to counteract SARS-CoV-2 binding to the transmembrane ACE2 receptor in target cells. Finally, we discuss potential drug resistance mechanisms and provide thoughts regarding clinical trial design to address the diversity in COVID-19 clinical manifestation. Of note, preventive vaccines, cell and gene therapies are not within the scope of the current review.

Keywords: ACE2; Antivirals; COVID-19; Drug development; Existing drugs; Immunomodulators; Monoclonal antibodies; Repurposed use; SARS-CoV-2; Spike protein; Therapeutic targets; Virus life cycle.

Fig. 1

Potential therapeutic targets for COVID-19 treatment. 1) SARS-CoV-2 attachment to host receptor ACE2, and release of genomic RNA, through cleavage with TMPRSS2 or endo-/lysosomal proteases characterizes initial infection. Several agents can be employed to inhibit these interactions including neutralizing antibodies, recombinant human soluble ACE2 (rhsACE2), protease inhibitors, and endosomal pH modulators (Fehr and Perlman, 2015). 2) Replication and translation of genomic RNA into structural proteins to assemble mature virions for release results in viral amplification and increases in infection. Antivirals inhibiting viral proteases and RdRp are being evaluated against this checkpoint (Fehr and Perlman, 2015). 3) Due to viral replication, host immune responses are triggered that can cause hyperactivation of immune cells and constant production of pro-inflammatory cytokines, resulting in more severe disease presentation (Cardone et al., 2020; Huang et al., 2020b). Novel and repurposed immunomodulators are under investigation to mitigate harmful immune responses. Angiotensin-converting enzyme 2 (ACE2); Transmembrane protease serine 2 (TMPRSS2); RNA-dependent RNA polymerase (RdRp); Main protease (Mpro); Papain-like protease (PLpro); IL (interleukin); Tumor necrosis factor α (TNFα).

Fig. 2

Therapies used in COVID-19 Clinical Trials. There are currently 2036 clinical trials that are registered as of 17 October 2020 with clinicaltrials.gov for interventional study for patients who have been diagnosed with COVID-19. (A) These trials list 396 different therapeutics as interventions, with the majority of the tested therapies of the small molecule family (73 %). Many of these drugs have been previously approved for other indications by at least one regulatory agency (e.g. US FDA, SFDA, EMEA, Health Canada, Japan MHLW, Ministry of Health of the Russian Federation, etc.). (B) Of the repurposed drugs, hydroxychloroquine (including hydroxychloroquine sulfate) is being studied in 176 clinical trials. (C) Novel therapeutics that are being developed, focus on preventing viral entry into the host cell through targeting the spike protein-ACE2 interaction with recombinant human soluble ACE2 proteins or anti-spike protein antibodies. A detailed listing of the therapies under clinical trial and development can be found in Table 1, Table 2. Data shown were derived from the U.S. National Library of Medicine ClinicalTrials.gov (access date 17 October 2020, search terms on interventional studies of “SARS-CoV-2″ and “COVID-19″). Data of listed clinical trials do not delineate between those that have been initiated, stopped, or have not started enrollment.