Nuclear Medicine in Times of COVID-19: How Radiopharmaceuticals Could Help to Fight the Current and Future Pandemics

Abstract

The emergence and global spread of COVID-19, an infectious disease caused by the novel coronavirus SARS-CoV-2, has resulted in a continuing pandemic threat to global health. Nuclear medicine techniques can be used for functional imaging of (patho)physiological processes at the cellular or molecular level and for treatment approaches based on targeted delivery of therapeutic radionuclides. Ongoing development of radiolabeling methods has significantly improved the accessibility of radiopharmaceuticals for in vivo molecular imaging or targeted radionuclide therapy, but their use for biosafety threats such as SARS-CoV-2 is restricted by the contagious nature of these agents. Here, we highlight several potential uses of nuclear medicine in the context of SARS-CoV-2 and COVID-19, many of which could also be performed in laboratories without dedicated containment measures. In addition, we provide a broad overview of experimental or repurposed SARS-CoV-2-targeting drugs and describe how radiolabeled analogs of these compounds could facilitate antiviral drug development and translation to the clinic, reduce the incidence of late-stage failures and possibly provide the basis for radionuclide-based treatment strategies. Based on the continuing threat by emerging coronaviruses and other pathogens, it is anticipated that these applications of nuclear medicine will become a more important part of future antiviral drug development and treatment.

Keywords: PET-based antiviral drug development; diagnostic radionuclides; molecular imaging of SARS-CoV-2; positron emission tomography (PET); radioimmunotherapy (RIT); radionuclide therapy of COVID-19; single photon emission computer tomography (SPECT); therapeutic radionuclides.

Figure A1

Structure of selected peptidomimetic SARS-CoV-2 Mpro inhibitors with electrophilic aldehyde (A) or α-ketoamide (B) warhead. For mechanism of action and pharmacological properties see Figure 5 and Table 2 in the main text.

Figure 1

Structure of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Schematic representation illustrating the 4 structural proteins of SARS-CoV-2. Inset shows side (left) and top (middle) view of homotrimeric spike glycoprotein with two of the receptor binding domains (RBD, red) in their down position and one in the up position. The rightmost structure shows a single monomer with the RBD in its up position and bound to human ACE2. Protein structures visualized with PyMol using models from https://swissmodel.expasy.org.

Figure 2

SARS-CoV-2 replication and transcription cycle in infected cells. Schematic representation of the processes involved in the replication of SARS-CoV-2 in infected host cells. For details see Section 2.2 and Section 2.3.

Figure 3

Mechanism of action and structure of small molecule ACE2 inhibitors. (A) Surface representation of the crystal structure of ACE2 with the small molecule inhibitor MLN-4760 (green) bound to the active site. Inset: close-up view showing part of the inhibitor bound to the active site. (B) Stick representation of MLN-4760 (green) bound to residues at the active site. Catalytic residues and the active site zinc ion are indicated in yellow. Dashed black lines indicate formation of hydrogen bonds. (C) Structure of different small molecule inhibitors of ACE2 and IC₅₀ values for suppression of human ACE2.

Figure 4

Structure–activity relationship of small molecule TMPRSS2 inhibitors. Shown are various synthetic inhibitors with sulfonylated 3-amindinophenylalanylamide moieties. For details and additional structures, see [42].

Figure 5

SARS-CoV-2 Mpro peptidomimetic inhibitors with different electrophilic warheads. (A) Surface representation of one protomer from the crystal structure of SARS-CoV-2 Mpro with the peptidomimetic inhibitor 11b (green) bound to the active site. Insets: close-up view of the active site after covalent modification by (from left to right) inhibitor 11b with an aldehyde warhead, α-ketoamide 13b with an α-ketoamide warhead or N3 with an acrylate warhead (green). Residues forming the catalytic dyad are indicated in turquoise (His₄₁) or orange (Cys₁₄₅) and hydrogen bonds are indicated by dashed black lines. (B) Stick representations of (from left to right) aldehyde inhibitor 11b, α-ketoamide 13b and acrylate N3 (green) covalently bound to the catalytic cysteine residue (orange). (C) Structure of (from left to right) aldehyde inhibitor 11b, α-ketoamide 13b and acrylate N3. For pharmacological properties see Table 2. For the structures of additional petidomimetic inhibitors with aldehyde or α-ketoamide warheads listed in Table 2, see Appendix A at the end of the article.

Figure 6

SARS-CoV-2 Mpro small molecule covalent inhibitors. (A) Surface representation of one protomer from the crystal structure of SARS-CoV-2 Mpro with the carmofur fatty acid moiety (green) bound to the active site. Inset: close-up view of the inhibitor-bound active site, with residues forming the catalytic dyad indicated in turquoise (His₄₁) or orange (Cys₁₄₅) and hydrogen bonds indicated by dashed black lines. (B) Stick representation of the fatty acid (FA) moiety of carmofur (green) covalently bound to the catalytic cysteine residue (orange). In addition, the 5-fluorouracil (5-FU) moiety released during binding of carmofur to the active site is also shown. (C) Structure of different small molecule covalent SARS-CoV-2 Mpro inhibitors. For pharmacological properties, see Table 2.

Figure 7

SARS-CoV-2 Mpro small molecule non-covalent inhibitors. (A) Surface representation of one protomer from the crystal structure of SARS-CoV-2 Mpro with baicalein (green) bound to the active site. Inset: close-up view of the inhibitor-bound active site, with residues forming the catalytic dyad indicated in turquoise (His₄₁) or orange (Cys₁₄₅) and hydrogen bonds indicated by dashed black lines. (B) Structure of different small molecule non-covalent SARS-CoV-2 Mpro inhibitors. For pharmacological properties, see Table 2.

Figure 8

SARS-CoV-2 PLpro small molecule non-covalent inhibitors. (A) Surface representation of the crystal structure of PLpro from SARS-CoV-2 with GRL-0617 (green) bound to the active site. Inset: close-up view of the inhibitor-bound active site, with residues forming the catalytic triad indicated in turquoise (His₂₇₂), orange (Cys₁₁₁) or purple (Asp₂₈₆) and hydrogen bonds indicated by dashed black lines. (B) Structure of different small molecule non-covalent SARS-CoV-2 PLpro inhibitors. For pharmacological properties, see Table 3.

Figure 9

SARS-CoV-2 PLpro peptidomimetic inhibitors with an electrophilic vinyl methyl ester warhead. (A) Surface representation of the crystal structure of PLpro from SARS-CoV-2 with VIR251 (green) bound to the active site. Inset: close-up view of the inhibitor-bound active site, with residues forming the catalytic triad indicated in turquoise (His₂₇₂), orange (Cys₁₁₁) or purple (Asp₂₈₆) and hydrogen bonds indicated by dashed black lines. (B) Stick representation of VIR251 (green) covalently bound to the catalytic cysteine residue (orange). (C) Structure of different peptidomimetic SARS-CoV-2 PLpro inhibitors with electrophilic vinyl methyl ester warhead. For pharmacological properties, see Table 3.

Figure 10

Overview of diagnostic and therapeutic nuclear medicine techniques. Shown are different types of radiation and their approximate linear energy transfer (middle) as well as their use for molecular imaging by PET and SPECT (top) or for targeted radionuclide therapy (bottom). Inset in the bottom left compares the tissue range of particles emitted by different types of therapeutic radionuclides with the size of SARS-CoV-2 virions and (infected) host cells.

Figure 11

Radiolabeling and targeting strategies for virus-specific imaging and/or radionuclide therapy. (A) Coupling of radionuclides to a suitable vehicle for delivery to the target structures can be achieved through direct radiolabeling of the vehicle (left), by conjugation of the vehicle with radiolabeled prosthetic groups (middle) or by conjugation of the vehicle with a chelator for radiometal complexation (right). (B) Delivery of radionuclides to virus-infected cells and/or the free virus could be achieved with (1) vehicles that are metabolized by virus-encoded non-structural proteins (NSPs) and selectively retained in infected cells, (2) vehicles that selectively bind to virus-encoded NSPs in infected cells or (3) vehicles that selectively bind to virus-encoded structural proteins (SPs) on the free virus and (for vehicles that can cross the cell membrane) in infected cells. (C) Theranostic radioligands are usually based on conjugation of a vehicle with a chelator for complexation of either diagnostic or therapeutic radiometals, allowing for application of the same conjugates for imaging and radionuclide therapy.