Nucleoside Analogs and Coronaviruses: History
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Subjects: Biochemistry & Molecular Biology | Chemistry, Medicinal | Infectious Diseases
Contributor:
Giovanni Roviello

Coronaviruses (CoVs) are positive-sense RNA enveloped viruses, members of the family Coronaviridae, that cause infections in a broad range of mammals including humans. Several CoV species lead to mild upper respiratory infections typically associated with common colds. However, three human CoV (HCoV) species: Severe Acute Respiratory Syndrome (SARS)-CoV-1, Middle East Respiratory Syndrome (MERS)-CoV, and SARS-CoV-2, are responsible for severe respiratory diseases at the origin of two recent epidemics (SARS and MERS), and of the current COronaVIrus Disease 19 (COVID-19), respectively.

  • coronavirus
  • SARS-CoV-1
  • SARS-CoV-2
  • MERS-CoV
  • nucleoside
  • remdesivir
  • lopinavir
  • ritonavir
  • favipiravir

1. Introduction

Coronaviruses (CoVs) are enveloped positive-sense single-stranded RNA viruses belonging to the family Coronaviridae, causing infections in avian species, mammals, and, among these, humans [1][2][3][4][5][6]. Human coronaviruses (HCoV) are believed to be of zoonotic origin, and their infections mainly lead to respiratory diseases [7][8][9]. In particular, HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1 cause the mild seasonal symptoms of the common cold [10][11]. However, three HCoV species responsible for the onset of life-threatening respiratory events emerged in the last two decades: Severe Acute Respiratory Syndrome (SARS)-CoV-1, Middle East Respiratory Syndrome (MERS)-CoV, and SARS-CoV-2 [12][13][14][15]. Human infection by SARS-CoV-2 is at the origin of the current COronaVIrus Disease 19 (COVID-19) pandemic. Interestingly, SARS-CoV-1 and MERS-CoV are more lethal but less transmissible than SARS-CoV-2, to which they are closely related [16]. There is clearly an urgent need for mass immunization and specific treatments for these HCoV-associated pathologies. CoV infection starts with the specific molecular recognition between the CoV spike (S) protein and host-specific receptors exposed on the surface of the target cells [17][18][19][20][21]. These have been identified for several CoVs and represent the primary molecular targets for anti-CoV strategies [22]. Human aminopeptidase N (APN) is involved in the infection by HCoV-229E; 9-O-acetylated sialic acid (9-O-Ac-Sia) receptor for HCoV-OC43 and HCoV-HKU1; angiotensin-converting enzyme 2 (ACE2) for HCoV-NL63, SARS-CoV-1, and SARS-CoV-2; dipeptidyl peptidase 4 (DPP4) for MERS-CoV [23][24]. Intracellularly, CoVs replicate their RNA and produce the viral proteins required for the assembly of new viral particles [25]. While five out of the seven HCoVs are usually associated with mild upper respiratory infections, MERS-CoV and SARS-CoV-1 and 2 can lead to lethal events [26]. In particular, the new SARS-CoV-2, first emerging in China at the end of 2019 [26], can provoke severe pneumonia, and being easily transmissible, it rapidly spread worldwide leading the World Health Organization (WHO) to declare COVID-19 a pandemic in March 2020 [27]. Currently, there have been more than two million deaths due to COVID-19 (2,239,418 as found in Worldometers.info [28] accessed on 1 February 2021), with enormous consequences for public health and the global economy [29][30][31]. While the whole world is fighting against COVID-19 and waits for a global and effective vaccination, the scientific community is devoting immense efforts to develop effective drugs for the immediate treatment of SARS-CoV-2 infection. Due to the urgent need for such a pharmacological treatment, drug repurposing [32][33] is one of the most common approaches. In this context, nucleobase-containing synthetic molecules [34][35][36][37][38][39][40] and modified nucleosides [41][42][43][44][45][46] are attracting significant interest for their antiviral activity [47][48][49]. In particular, nucleoside-mimicking analogs [50], as well as nucleoside precursors [51][52], being able to inhibit the growth of viruses, play a pivotal role in the search of effective therapies for HCoV infectious diseases [53][54].

2. Human Coronaviruses

Presently, seven HCoVs are known and described in the scientific literature [55]. Besides the well-known potentially lethal SARS-CoV-1, MERS-CoV, and SARS-CoV-2, the common human coronaviruses HCoV-229E, HCoV-NL63, HCoV-OC43, and HCoV-HKU1 identified in the last few decades were classified into two CoV genera: Alphacoronavirus and Betacoronavirus [56].
HCoV-229E and HCoV-NL63, belonging to the genus Alphacoronavirus [57], are genetically related to each other and are responsible for about 5% of all respiratory infections in hospitalized children [58]. Both HCoV-OC43 and HCoV-HKU1, of the genus Betacoronavirus [59], are ‘common cold’ viruses widely circulating worldwide, with associated severity of respiratory symptoms being documented only in rare cases [60]. Even though these HCoVs do not cause severe clinical symptoms in most patients, HCoV 229E and OC43 can provoke pneumonia [61][62], while HCoV-NL63 and HCoV-HKU1 infection lead in some cases also to bronchiolitis and croup [63][64].

Human Coronaviruses Causing Lethal Pneumonia: SARS-CoV-1, MERS-CoV, and SARS-CoV-2

The first HCoV-recognized pandemic, known as ‘Severe Acute Respiratory Syndrome’ (SARS), was caused by SARS-CoV-1 in China in 2002–2003 [65][66]. It spread to 29 countries worldwide, infecting over 8,000 people, with a 10% death rate [67]. Another deadly coronavirus emerged about ten years later, leading to the so-called ‘Middle East Respiratory Syndrome’ (MERS) and was indicated, thus, MERS-CoV [68]. After its outbreak in Jordan among hospital workers, it spread to Saudi Arabia in 2013–2014 [69]. MERS occurs predominantly in male individuals, while the same is not seen for SARS. The main clinical symptoms of both SARS and MERS include fever, cough, shortness of breath, and respiratory illness, with MERS being associated with more severe pneumonia and a higher mortality rate of up to 35% vs. the already-cited 10% of SARS [70]. Both MERS and SARS affect mainly adult individuals with a median age range of 39–50 years [62]. SARS-CoV-2 is closely related to SARS-CoV-1, with which it shares about 79% genome sequence identity, and is responsible for the current COVID-19 [71].
Like SARS-CoV-1 and MERS-CoV, SARS-CoV-2 belongs to the genus Betacoronavirus, but while the two SARS-CoVs are further classified into the Sarbecovirus subgenus, MERS-CoV belongs to the Merbecovirus subgenus [72]. Globally, the WHO estimated a mortality rate due to COVID-19 of 3.4%, though there is no definitive consensus on this estimate [73]. Whatever the mortality rate of SARS-CoV-2, one of the most worrying aspects of this virus is that it spreads easily and rapidly, having reached in a few months hundreds of countries infecting more than 100 million individuals.

3. Prophylaxis and Therapy of HCoV Diseases

Before 2002, the only known HCoVs were the common human coronaviruses associated with ‘common cold’ symptoms mentioned above. Since most people with an illness caused by them usually recovered spontaneously, there was typically no need for any drugs other than aspirin to relieve the cold-associated symptoms. Conversely, the critical clinical conditions often observed in patients affected by the highly pathogenic MERS-CoV, SARS-CoV-1, and, especially, SARS-CoV-2 recalled the urgency of developing vaccines and antiviral treatments for HCoV infections. This research theme was previously almost ignored by pharmaceutical companies and, in our opinion, should not be abandoned by the scientific community even when the COVID-19 emergency will be over. In SARS-CoV-1 infection, scientists undertook initial vaccine studies, but the obtained candidates presented severe complications such as immune disease insurgence in treated animals [74]. The research for other SARS vaccines was discontinued not only for the difficulties encountered, but mainly because SARS-CoV-1 vanished [74]. Owing to the pharmacological strategies adopted by physicians for SARS patients, these were essentially empirical and involved repurposed immunomodulatory and antiviral drugs, such as corticosteroids, lopinavir/ritonavir, and ribavirin [32][33]. Concerning MERS, despite several efforts to search for effective vaccines, antibodies, and drugs, no conclusive results were achieved. Repurposed drugs used with some success for MERS include again lopinavir/ritonavir and ribavirin [75][76]. After this premise, it appears clear how the lack of any useful vaccine and drug against SARS-CoV-1 and MERS-CoV was reflected in the current crisis, considering the relatively close relationship between SARS-CoV-1 and SARS-CoV-2 genomes, as well as the conserved nature of MERS and SARS-CoV-2 proteins [71]. Fortunately, academic institutions and pharmaceutical companies have lately developed some promising vaccine candidates against SARS-CoV-2. Among them, the Pfizer-BioNTech (BNT162b2) [77], the Moderna (mRNA-1273) [78], and the Oxford University/AstraZeneca (ChAdOx1-S) [79] vaccines were authorized for prophylaxis of COVID-19, while several others are currently in late-stage clinical testing [80]. Vaccines may represent a medium/long-term solution to the current pandemic, but short-term solutions such as pharmacological treatments against SARS-CoV-2 remain urgently needed. Presently, SARS-CoV-2 infection therapy includes immunomodulatory drugs, plasma from individuals recovered from COVID-19, and several pharmacological treatments [81]. In this regard, despite numerous repurposed drugs being tested, only the nucleoside analog remdesivir has been officially approved by the American Food and Drug Administration (FDA) agency to date [82].

4. Protein Targets for Anti-HCoV Pharmaceutical Strategies

Amongst the coronavirus targets that were studied, or are currently being investigated, in the fight against the three most pathogenic HCoVs, particular relevance is given to the spike (S) protein [17][18][19][20][21], RNA-dependent RNA-polymerase (RdRp) [83][84][85][86][87], papain-like protease (PLpro) [88][89] and main protease (Mpro, 3CLpro) [90][91]. In particular, this latter, which proteolytically cleaves the polyproteins to functional proteins essential for viral replication, occupies a special place in pharmaceutical research [92]. Hence, the frequently-reported administration of potential Mpro inhibitors like lopinavir and ritonavir to SARS, MERS, and COVID patients [76][93][94], even though there is no agreement on the real efficacy of this cocktail therapy, especially in the case of the current pandemic [94]. RdRp is a protein involved in SARS-CoV-2 replication, considered to be conserved within RNA viruses [95]. Targeting the RdRp by antiviral drugs could be a potential therapeutic option to inhibit coronavirus RNA polymerization and, consequently, viral replication. Since remdesivir [82], the only FDA-approved drug for COVID-19 available to date, is believed to inhibit SARS-CoV-2 RNA polymerase competing with natural nucleotide triphosphates for incorporation into growing viral RNA, this aspect attracts interest not only on this drug but also on other analogs of nucleosides and nucleoside precursors with similar RdRp inhibitory activity.

5. Synthetic Nucleoside Precursors for HCoV Disease Therapy

Among the synthetic drugs under scrutiny in the treatment of viral respiratory pathologies, nucleoside precursors occupy an important place, especially in the present COVID-19 pandemic [54]. Here below, we report on the main nucleoside precursors evaluated as anti-HCoV drugs (Figure 1).
Molecules 26 00986 g001 550
Figure 1. Structures of the nucleoside precursors and derivatives of purine analogs (with drug names and related IUPAC nomenclature) used or under investigation in the HCoV disease therapy.

This entry is adapted from the peer-reviewed paper 10.3390/molecules26040986

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