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Role of ACE2 receptor and the landscape of treatment options from convalescent plasma therapy to the drug repurposing in COVID-19 - PubMed

Review

Role of ACE2 receptor and the landscape of treatment options from convalescent plasma therapy to the drug repurposing in COVID-19

Pravindra Kumar et al. Mol Cell Biochem. 2021 Feb.

Abstract

Since the first case reports in Wuhan, China, the SARS-CoV-2 has caused a pandemic and took lives of > 8,35,000 people globally. This single-stranded RNA virus uses Angiotensin-converting enzyme 2 (ACE2) as a receptor for entry into the host cell. Overexpression of ACE2 is mainly observed in hypertensive, diabetic and heart patients that make them prone to SARS-CoV-2 infection. Mitigations strategies were opted globally by the governments to minimize transmission of SARS-CoV-2 via the implementation of social distancing norms, wearing the facemasks, and spreading awareness using digital platforms. The lack of an approved drug treatment regimen, and non-availability of a vaccine, collectively posed a challenge for mankind to fight against the SARS-CoV-2 pandemic. In this scenario, repurposing of existing drugs and old treatment options like convalescent plasma therapy can be one of the potential alternatives to treat the disease. The drug repurposing provides a selection of drugs based on the scientific rationale and with a shorter cycle of clinical trials, while plasma isolated from COVID-19 recovered patients can be a good source of neutralizing antibody to provide passive immunity. In this review, we provide in-depth analysis on these two approaches currently opted all around the world to treat COVID-19 patients. For this, we used "Boolean Operators" such as AND, OR & NOT to search relevant research articles/reviews from the PUBMED for the repurposed drugs and the convalescent plasma in the COVID-19 treatment. The repurposed drugs like Chloroquine and Hydroxychloroquine, Tenofovir, Remdesivir, Ribavirin, Darunavir, Oseltamivir, Arbidol (Umifenovir), Favipiravir, Anakinra, and Baricitinib are already being used in clinical trials to treat the COVID-19 patients. These drugs have been approved for a different indication and belong to a diverse category such as anti-malarial/anti-parasitic, anti-retroviral/anti-viral, anti-cancer, or against rheumatoid arthritis. Although, the vaccine would be an ideal option for providing active immunity against the SARS-CoV-2, but considering the current situation, drug repurposing and convalescent plasma therapy and repurposed drugs are the most viable option against SARS-CoV-2.

Keywords: ARDS; Cytokine storm syndrome; Herd immunity; Rheumatoid arthritis; Vaccine nationalism; Vertical transmission.

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Conflict of interest statement

Authors declare no potential conflicts of interest and also no competing financial interest associated with this manuscript.

Figures

Fig. 1
Fig. 1

Classification of RNA-based viruses and flow-chart showing the belongingness of Coronavirus and other closely related RNA viruses. This schematic classification of the Coronaviridae family shows how the members are divided based on sense and anti-sense strands. SARS-CoV-2 falls in category of single stranded sense strand RNA virus that is enveloped and possesses helical capsid. The α-coronaviruses are: 229E and NL63. Except SARS-CoV-2, there are other members of the β-coronavirus types are: OC43, HKU1, SARS-CoV, and MERS-CoV

Fig. 2
Fig. 2

Structure of the SARS-CoV-2 virus. An RNA virus, SARS-CoV-2 consists of an envelope (E), membrane (M), spike (S), and nucleocapsid (N) proteins. The RNA is single positive-sense strand. Among those, M, S and E are glycoproteins in nature. The viral nucleo-capsid is made of proteinaceous coat capsid, inside which RNA and non-histone protein reside. SARS-CoV-2 also contains shorter spikes that possess hemagglutinin-esterase (HE) protein; their size is larger in case of Toroviruses

Fig. 3
Fig. 3

Protein architecture of ACE2, TMPRSS2, and DPP4. a TMPRSS2 is a protease which consists of four domains LDLA, SR, TRYPSIN, and TM domain (b) ACE2, an enzyme possess one TM domain and one signal peptide, c DPP4 or CD26 is a protease which contains one signal peptide

Fig. 4
Fig. 4

ACE2 Expression across major normal human organs. The RNAseq derived data shows expression of ACE2 transcript across different organs including colon, duodenum, gall bladder, heart, kidney, liver, lung, small intestine, stomach, testis and thyroid. The value of expression is shown in form of Reads Per Kilobase of transcript, per million mapped reads (RPKM), which is a normalized unit for denoting transcript expression

Fig. 5
Fig. 5

Major sites of ACE2 expression, Binding of SARS-CoV-2 to ACE2 receptor, and involvement of TMPRSS2, and DPP4 in SARS-CoV-2 entry. The spike protein (S) helps SARS-CoV-2 to enter into the host cell via binding to its receptor Angiotensin Converting Enzyme 2 (ACE2) that is part of the renin–angiotensin–aldosterone system (RAAS). RAAS and its component include angiotensinogen (AGT), the enzyme renin, angiotensin converting enzyme (ACE), and their hydrolytic products angiotensins I and II. Once SARS-CoV-2 binds to ACE2, it internalize through the process of endocytosis into the cells, which leads to downregulation of membrane-anchored ACE2. A decrease in ACE2 levels led to organ damage via activation and deactivation of ACE/Ang II/AT1R & ACE2/Ang-(1–7)/Mas-R pathways, respectively. There is alternate route of infection of SARS-CoV-2 is via transmembrane protease serine 2 (TMPRSS2) driven cleavage of SARS-CoV-2 escorted through ACE2. Due to this membrane shedding of ACE2 occurs by disintegrin and MMP17. Furthermore, soluble form of ACE2 obstructs SARS-CoV-2 from binding to membrane-anchored ACE2 in plasma membrane. An increased amount of soluble ACE2 and expression induced due to RAS inhibitors could be advantageous for protecting lungs and other organ injury but not infection with SARS-CoV-2

Fig. 6
Fig. 6

Schema for screening of the articles reporting drugs repurposed for COVID-19 The NCBI search engine was searched using Boolean operators such as AND, NOT, & OR. The articles were fetched for repurposing drugs, synergism or convalescent plasma in combination with COVID-19. The articles were further segregated based on the agent used for drug repurposing

Fig. 7
Fig. 7

The chemical structure of the repurposed drugs for treatment of the COVID-19 patients. A number of drugs including anti-malarial/anti-parasitic (Chloroquine, hydroxychloroquine, and emetine), anti-myelofibrosis (Ruxolitinib), anti-viral/anti-retroviral (Tenofovir, Lopinavir, Ritonavir, Baloxavir, Remdesivir, Ribavirin, Darunavir, Oseltamivir, Arbidol, and Favipiravir), and anti-rheumatoid arthritis (Anakinra, Barcitinib, Methylprednisolone, Naproxene, and Tofacitinib) are the drugs that have been extensively in use for the treatment of COVID-19 patients

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