Tissue‐ and cell‐expression of druggable host proteins provide insights into repurposing drugs for COVID‐19

Abstract

Several human host proteins play important roles in the lifecycle of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). Many drugs targeting these host proteins have been investigated as potential therapeutics for coronavirus disease 2019 (COVID‐19). The tissue‐specific expressions of selected host proteins were summarized using proteomics data retrieved from the Human Protein Atlas, ProteomicsDB, Human Proteome Map databases, and a clinical COVID‐19 study. Protein expression features in different cell lines were summarized based on recent proteomics studies. The half‐maximal effective concentration or half‐maximal inhibitory concentration values were collected from in vitro studies. The pharmacokinetic data were mainly from studies in healthy subjects or non‐COVID‐19 patients. Considerable tissue‐specific expression patterns were observed for several host proteins. ACE2 expression in the lungs was significantly lower than in many other tissues (e.g., the kidneys and intestines); TMPRSS2 expression in the lungs was significantly lower than in other tissues (e.g., the prostate and intestines). The expression levels of endocytosis‐associated proteins CTSL, CLTC, NPC1, and PIKfyve in the lungs were comparable to or higher than most other tissues. TMPRSS2 expression was markedly different between cell lines, which could be associated with the cell‐dependent antiviral activities of several drugs. Drug delivery receptor ICAM1 and CTSB were expressed at a higher level in the lungs than in other tissues. In conclusion, the cell‐ and tissue‐specific proteomics data could help interpret the in vitro antiviral activities of host‐directed drugs in various cells and aid the transition of the in vitro findings to clinical research to develop safe and effective therapeutics for COVID‐19.

Recent Advancement in Anticancer Compounds from Marine Organisms: Approval, Use and Bioinformatic Approaches to Predict New Targets

“…Differentially expressed genes associated with panobinostat were detected, indicating its metabolic role in different diseases. Plitidepsin was another analyzed molecule, and it represents a concrete example of a re-proposed drug used recently for the treatment of COVID-19 unlike other re-proposed drugs, such as lopinavir–ritonavir, hydroxychloroquine, remdesivir and interferon beta 1a, which were supposed to be inefficient [ 131 , 132 ]. Consulting the tools, many broad-spectrum plitidepsin-related biological activities were detected to be in line with previous findings [ 55 ].…”

“…As we can see in Figure 3 A, the higher bar size is represented by the category of genes that regulate the cytoplasmatic sequestering of transcription factors, suggesting that panobinostat selectively is able to interact with specific transcription factors in the cytoplasm, which might be considered a predictive effect of this molecule in this specific biological compartment. For example, panobinostat is involved in the regulation of transcription factors present in the HOXA cluster, which are under the control of the mixed-lineage leukemia (MLL) complex, whose proteins are fused or mutated through interactions with many cofactors [ 131 ].…”

Differential Bioactivation Profiles of Different GS-441524 Prodrugs in Cell and Mouse Models: ProTide Prodrugs with High Cell Permeability and Susceptibility to Cathepsin A Are More Efficient in Delivering Antiviral Active Metabolites to the Lung

“…There are mainly two prodrug design strategies for boosting cell membrane permeability and bioavailability of nucleoside analogues. One is covering hydrophilic groups like hydroxyl groups (-OH) on the ribose sugar moiety with ester moieties, which will improve the lipophilicity. , An example employing this strategy is GS-621763, which covers the three -OH groups with isopropyl esters. , In this case, parent nucleoside analogue GS-441524 (Nuc) itself is the major compound present in the systemic circulation after oral administration because the liver has abundant esterases that can cleave ester moieties and thus convert an ester prodrug back to Nuc. ,, Another strategy is using a monophosphate nucleoside (MP-Nuc) as the starting point and adding ester and other hydrophobic moieties to cover the -OH group on the phosphate group, such as the nucleoside phosphoramidate (ProTide) prodrug. ProTides can load MP-Nuc into cells after ester hydrolysis by intracellular esterases, bypassing the slow and rate-limiting first phosphorylation step that is needed for Nuc.…”