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Papers by Zheng Yao Low

Journal of Cellular Biochemistry, 2024

The 14-3-3 family of proteins are highly conserved acidic eukaryotic proteins (25-32 kDa) abundan... more The 14-3-3 family of proteins are highly conserved acidic eukaryotic proteins (25-32 kDa) abundantly present in the body. Through numerous binding partners, the 14-3-3 is responsible for many essential cellular pathways, such as cell cycle regulation and gene transcription control. Hence, its dysregulation has been linked to the onset of critical illnesses such as cancers, neurodegenerative diseases and viral infections. Interestingly, explorative studies have revealed an inverse correlation of 14-3-3 protein in cancer and neurodegenerative diseases, and the direct manipulation of 14-3-3 by virus to enhance infection capacity has dramatically extended its significance. Of these, COVID-19 has been linked to the 14-3-3 proteins by the interference of the SARS-CoV-2 nucleocapsid (N) protein during virion assembly. Given its predisposition towards multiple essential host signalling pathways, it is vital to understand the holistic interactions between the 14-3-3 protein to unravel its potential therapeutic unit in the future. As such, the general structure and properties of the 14-3-3 family of proteins, as well as their known biological functions and implications in cancer, neurodegeneration, and viruses, were covered in this review. Furthermore, the potential therapeutic target of 14-3-3 proteins in the associated diseases was discussed.

Viruses, Jun 20, 2022

Molnupiravir is a β-d-N4-hydroxycytidine-5′-isopropyl ester (NHC) compound that exerts antiviral ... more Molnupiravir is a β-d-N4-hydroxycytidine-5′-isopropyl ester (NHC) compound that exerts antiviral activity against various RNA viruses such as influenza, SARS, and Ebola viruses. Thus, the repurposing of Molnupiravir has gained significant attention for combatting infection with SARS-CoV-2, the etiological agent of COVID-19. Recently, Molnupiravir was granted authorization for the treatment of mild-to-moderate COVID-19 in adults. Findings from in vitro experiments, in vivo studies and clinical trials reveal that Molnupiravir is effective against SARS-CoV-2 by inducing viral RNA mutagenesis, thereby giving rise to mutated complementary RNA strands that generate non-functional viruses. To date, the data collectively suggest that Molnupiravir possesses promising antiviral activity as well as favorable prophylactic efficacy, attributed to its effective mutagenic property of disrupting viral replication. This review discusses the mechanisms of action of Molnupiravir and highlights its clinical utility by disabling SARS-CoV-2 replication, thereby ameliorating COVID-19 severity. Despite relatively few short-term adverse effects thus far, further detailed clinical studies and long-term pharmacovigilance are needed in view of its mutagenic effects.

Reviews in Medical Virology, Sep 21, 2021

The family of Suppressor of Cytokine Signalling (SOCS) proteins plays pivotal roles in cytokine a... more The family of Suppressor of Cytokine Signalling (SOCS) proteins plays pivotal roles in cytokine and immune regulation. Despite their key roles, little attention has been given to the SOCS family as compared to other feedback regulators. To date, SOCS proteins have been found to be exploited by viruses such as herpes simplex virus (HSV), hepatitis B virus (HBV), hepatitis C virus (HCV), Zika virus, respiratory syncytial virus (RSV), Ebola virus, influenza A virus (IAV) and SARS‐CoV, just to name a few. The hijacking and subsequent upregulation of the SOCS proteins upon viral infection, suppress the associated JAK‐STAT signalling activities, thereby reducing the host antiviral response and promoting viral replication. Two SOCS protein family members, SOCS1 and SOCS3 are well‐studied and their roles in the JAK‐STAT signalling pathway are defined as attenuating interferon (IFN) signalling upon viral infection. The upregulation of SOCS protein by SARS‐CoV during the early stages of infection implies strong similarity with SARS‐CoV‐2, given their closely related genomic organisation. Thus, this review aims to outline the plausibility of SOCS protein inhibitors as a potential therapeutic regimen for COVID‐19 patients. We also discuss the antagonists against SOCS protein to offer an overview on the previous ‘successes’ of SOCS protein inhibition in various viral infections that may portray possible clues for COVID‐19 disease management.

Viruses, Sep 8, 2022

Coronavirus disease 2019 (COVID-19) has caused an unprecedented global crisis and continues to th... more Coronavirus disease 2019 (COVID-19) has caused an unprecedented global crisis and continues to threaten public health. The etiological agent of this devastating pandemic outbreak is the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). COVID-19 is characterized by delayed immune responses, followed by exaggerated inflammatory responses. It is well-established that the interferon (IFN) and JAK/STAT signaling pathways constitute the first line of defense against viral and bacterial infections. To achieve viral replication, numerous viruses are able to antagonize or hijack these signaling pathways to attain productive infection, including SARS-CoV-2. Multiple studies document the roles of several non-structural proteins (NSPs) of SARS-CoV-2 that facilitate the establishment of viral replication in host cells via immune escape. In this review, we summarize and highlight the functions and characteristics of SARS-CoV-2 NSPs that confer host immune evasion. The molecular mechanisms mediating immune evasion and the related potential therapeutic strategies for controlling the COVID-19 pandemic are also discussed.

Virus Genes, Jun 1, 2021

The Coronavirus Disease 2019 (COVID-19), a pneumonic disease caused by the SARS Coronavirus 2 (SA... more The Coronavirus Disease 2019 (COVID-19), a pneumonic disease caused by the SARS Coronavirus 2 (SARS-CoV-2), is the 7th Coronavirus to have successfully infected and caused an outbreak in humans. Genome comparisons have shown that previous isolates, the SARS-related coronavirus (SARSr-CoV), including the SARS-CoV are closely related, yet different in disease manifestation. Several explanations were suggested for the undetermined origin of SARS-CoV-2, in particular, bats, avian and Malayan pangolins as reservoir hosts, owing to the high genetic similarity. The general morphology and structure of all these viral isolates overlap with analogous disease symptoms such as fever, dry cough, fatigue, dyspnoea and headache, very similar to the current SARS-CoV-2. Chest CT scans for SARS-CoV-2, SARS-CoV and MERS-CoV reveal pulmonary lesions, bilateral ground-glass opacities, and segmental consolidation in the lungs, a common pathological trait. With greatly overlapping similarities among the previous coronavirus, the SARS-CoV, it becomes interesting to observe marked differences in disease severity of the SARS-CoV-2 thereby imparting it the ability to rapidly transmit, exhibit greater stability, bypass innate host defences, and increasingly adapt to their new host thereby resulting in the current pandemic. The most recent B.1.1.7, B.1.351 and P.1 variants of SARS-CoV-2, highlight the fact that changes in amino acids in the Spike protein can contribute to enhanced infection and transmission efficiency. This review covers a comparative analysis of previous coronavirus outbreaks and highlights the differences and similarities among different coronaviruses, including the most recent isolates that have evolved to become easily transmissible with higher replication efficiency in humans.

Current Research in Microbial Sciences, 2023

Influenza virus infection, more commonly known as the 'cold flu', is an etiologic... more Influenza virus infection, more commonly known as the 'cold flu', is an etiological agent that gives rise to recurrent annual flu and many pandemics. Dated back to the 1918-Spanish Flu, the influenza infection has caused the loss of many human lives and significantly impacted the economy and daily lives. Influenza virus can be classified into four different genera: influenza AD , with the former two, influenza A and B, relevant to humans. The capacity of antigenic drift and shift in Influenza A has given rise to many novel variants, rendering vaccines and antiviral therapies useless. In light of the emergence of a novel betacoronavirus, the SARS-CoV-2, unravelling the underpinning mechanisms that support the recurrent influenza epidemics and pandemics is essential. Given the symptom similarities between influenza and covid infection, it is crucial to reiterate what we know about the influenza infection. This review aims to describe the origin and evolution of influenza infection. Apart from that, the risk factors entail the implication of co-infections, especially regarding the COVID-19 pandemic is further discussed. In addition, antiviral strategies, including the potential of drug repositioning, are discussed in this context. The diagnostic approach is also critically discussed in an effort to understand better and prepare for upcoming variants and potential influenza pandemics in the future. Lastly, this review encapsulates the challenges in curbing the influenza spread and provides insights for future directions in influenza management.

Viruses

The COVID-19 pandemic caused by SARS-CoV-2 is associated with a lower fatality rate than its SARS... more The COVID-19 pandemic caused by SARS-CoV-2 is associated with a lower fatality rate than its SARS and MERS counterparts. However, the rapid evolution of SARS-CoV-2 has given rise to multiple variants with varying pathogenicity and transmissibility, such as the Delta and Omicron variants. Individuals with advanced age or underlying comorbidities, including hypertension, diabetes and cardiovascular diseases, are at a higher risk of increased disease severity. Hence, this has resulted in an urgent need for the development of better therapeutic and preventive approaches. This review describes the origin and evolution of human coronaviruses, particularly SARS-CoV-2 and its variants as well as sub-variants. Risk factors that contribute to disease severity and the implications of co-infections are also considered. In addition, various antiviral strategies against COVID-19, including novel and repurposed antiviral drugs targeting viral and host proteins, as well as immunotherapeutic strateg...

Expert Reviews in Molecular Medicine, 2022

The current COVID-19 pandemic contributed by the SARS-CoV-2 has put in place an urgent need for n... more The current COVID-19 pandemic contributed by the SARS-CoV-2 has put in place an urgent need for new and promising antiviral therapeutics. The viral RNA-dependent RNA polymerase (RdRp) enzyme plays a vital role in viral replication for all RNA viruses, including SARS-CoV-2, thereby making it a prime and promising candidate for novel antiviral targeting. Interestingly, the human telomerase reverse transcriptase (hTERT), a common catalytic subunit of the telomerase enzyme in many cancers, has also been identified with structural and functional similarities to the viral RdRp. Therefore, it becomes essential to evaluate and consider anticancer drugs that target hTERT towards antiviral RdRp activity, and vice versa. For instance, Floxuridine, an hTERT inhibitor, and VX-222, a hepatitis C virus RdRp inhibitor, are now gaining recognition as a potential antiviral against SARS-CoV-2 and anti-hTERT for cancer, simultaneously. While limited studies on hTERT inhibitors for use as viral RdRp, an...

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2021

Ivermectin (IVM) is an FDA approved macrocyclic lactone compound traditionally used to treat para... more Ivermectin (IVM) is an FDA approved macrocyclic lactone compound traditionally used to treat parasitic infestations and has shown to have antiviral potential from previous in-vitro studies. Currently, IVM is commercially available as a veterinary drug but have also been applied in humans to treat onchocerciasis (river blindness - a parasitic worm infection) and strongyloidiasis (a roundworm/nematode infection). In light of the recent pandemic, the repurposing of IVM to combat SARS-CoV-2 has acquired significant attention. Recently, IVM has been proven effective in numerous in-silico and molecular biology experiments against the infection in mammalian cells and human cohort studies. One promising study had reported a marked reduction of 93% of released virion and 99.98% unreleased virion levels upon administration of IVM to Vero-hSLAM cells. IVM's mode of action centres around the inhibition of the cytoplasmic-nuclear shuttling of viral proteins by disrupting the Importin heterodimer complex (IMPα/β1) and downregulating STAT3, thereby effectively reducing the cytokine storm. Furthermore, the ability of IVM to block the active sites of viral 3CLpro and S protein, disrupts important machinery such as viral replication and attachment. This review compiles all the molecular evidence to date, in review of the antiviral characteristics exhibited by IVM. Thereafter, we discuss IVM's mechanism and highlight the clinical advantages that could potentially contribute towards disabling the viral replication of SARS-CoV-2. In summary, the collective review of recent efforts suggests that IVM has a prophylactic effect and would be a strong candidate for clinical trials to treat SARS-CoV-2.

Viruses, 2020

Traditionally, drug discovery utilises a de novo design approach, which requires high cost and ma... more Traditionally, drug discovery utilises a de novo design approach, which requires high cost and many years of drug development before it reaches the market. Novel drug development does not always account for orphan diseases, which have low demand and hence low-profit margins for drug developers. Recently, drug repositioning has gained recognition as an alternative approach that explores new avenues for pre-existing commercially approved or rejected drugs to treat diseases aside from the intended ones. Drug repositioning results in lower overall developmental expenses and risk assessments, as the efficacy and safety of the original drug have already been well accessed and approved by regulatory authorities. The greatest advantage of drug repositioning is that it breathes new life into the novel, rare, orphan, and resistant diseases, such as Cushing’s syndrome, HIV infection, and pandemic outbreaks such as COVID-19. Repositioning existing drugs such as Hydroxychloroquine, Remdesivir, I...

Books by Zheng Yao Low

Drug Repurposing for Emerging Infectious Diseases and Cancer, 2023

The high infection capacity and rapid mutations in coronavirus disease 2019 (COVID-19) has been n... more The high infection capacity and rapid mutations in coronavirus disease 2019 (COVID-19) has been no stranger to many. The etiological agent that contributed to this global health crisis is by no means the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). COVID-19 is characterized by an episode of immune fluctuations, followed by hyperactivation of inflammatory responses, known as the cytokine storm. The rapid progression of the COVID-19 pandemic calls for new and promising antiviral therapeutics. Repositioning anticancer drugs against the virus is very much explored due to the common similar pathways or targeting structures, opening new windows for many possibilities. As such, the repurposing of zidovudine for Friend leukemia virus and ouabain for Ebola virus are among the successful examples. Other potential FDA-approved anticancer drugs to be repositioned for COVID-19 include imatinib, saracatinib, and homoharringtonine, which have been studied for other coronaviruses in the past. Furthermore, current anticancer drugs like carmofur, carfilzomib, zotatifin, plitidepsin, and toremifene have gained interesting outcomes with respect to SARS-CoV-2. It is well recognized that to achieve viral replication, viruses antagonise or hijack host proteins and signaling pathways to gain productive infection, with SARS-CoV-2 indeed being no exception. This review aims to discuss the drug repositioning approaches concerning previously established anticancer drugs on viruses, especially on SARS-CoV-2. We accentuate this idea with specific examples of how potential anticancer inhibitors can effectively be used against SARS-CoV-2 as well as the limitations and future perspectives of drug repositioning.

WORLD SCIENTIFIC eBooks, Oct 1, 2022

On 30 January 2020, the World Health Organization (WHO) characterized the novel severe acute resp... more On 30 January 2020, the World Health Organization (WHO) characterized the novel severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) outbreak as a Public Health Emergency of International Concern. Subsequently, on 11 March 2020, WHO declared the global spread of Coronavirus disease 2019 (COVID-19) as a pandemic triggered by this causative virus. This COVID-19 pandemic has impacted lives and livelihoods worldwide, resulting in unprecedented social disruption and economic losses. In order to design and develop effective diagnostics, vaccines and therapeutic interventions against SARS-CoV-2, it is imperative to understand the molecular and cellular mechanisms underpinning the complex interactions between this virus, its variants, and its infected hosts. This chapter provides an overview on the classification, genomic organization and evolution of SARS-CoV-2 (including the emergence of variants from Alpha to Omicron), and summarizes existing and emerging testing strategies. With unprecedented speed, an array of conventional and new COVID-19 vaccines has been developed, evaluated in clinical trials, and administered to billions worldwide. Current and novel antiviral drugs and immunomodulatory approaches are discussed for the therapeutic and prophylactic management of SARS-CoV-2 infections. Finally, much remains for humanity to discover and learn as the world must continue to adapt and live with endemic COVID-19 and SARS-CoV-2 evolution.

Biomedical Translational Research, 2022

Drug treatments of certain diseases that are either rare, complex, or novel may not always be ava... more Drug treatments of certain diseases that are either rare, complex, or novel may not always be available due to high cost of drug development and research. Drug repositioning (DR) is an alternative approach to usurp already available drugs or drug candidates with FDA approval, which have been initially developed for specific diseases and re-establish their use for other diseases. Modern genomic methods for drug repositioning involve the usage of computational programs and online tools to analyse and ultimately deduce targets with high specificity to be considered as candidates for repositioning. Gene, protein, disease, and drug databases are built from high-throughput experimental, in vitro, in vivo, and clinical data, thus providing a reliable basis for drug target acquisition purposes. Key experimental and in silico approaches for modern drug repositioning, namely, signature matching, molecular docking, genome-wide association studies, and network-based approaches aided by artificial intelligence will be described in this chapter along with research examples that have used these methods. Drug repositioning for certain diseases, such as Alzheimer’s disease, cystic fibrosis, and SARS-CoV-2 disease, will be discussed in this chapter. Lastly, we will discuss the challenges faced and the future perspectives of DR. Genomic computational approaches for drug repositioning presents much potential in identifying drug targets more efficiently and effectively, which provides the opportunity to fulfil the gap for treatment of diseases with little or no cure.

CRC Press eBooks, Jun 15, 2023

Introduction Coronavirus, a zoonotic virus that falls under the Coronaviridae family, is commonl... more Introduction
Coronavirus, a zoonotic virus that falls under the Coronaviridae family, is commonly found in avian species and mammals, such as masked palm civets, bats, and camels (Gong & Bao, 2018). There are four genera under the Coronaviridae family, namely, the alpha, beta, gamma, and delta-coronaviruses, in which the beta- coronavirus contribute to severe respiratory disease and numerous fatalities (Velavan & Meyer, 2020). Being a well- known source of respiratory- associated illness, the coronavirus is no stranger to the primary root of the common cold, accounting for up to 20% of all human common cold cases (Thiel et al., 2001). Before the emergence of the severe acute respiratory syndrome (SARS- CoV) in 2002 and Middle East Respiratory Syndrome (MERS- CoV) in 2012, the coronavirus was deemed to affect only immunocompromised individuals, causing mild illness (Zhong et al., 2003; Nature Research Custom Media, 2021). To date, seven strains of coronaviruses have been reported to cause disease in humans. Amongst these strains, the HCoV- OC43, HCoV-229E, HCoV- HKU1 and HCoV- NL63 give rise to the common cold and mild respiratory infections. In contrast, the SARS- CoV, MERS- CoV, and the recent SARS- CoV- 2 (causative virus for the COVID- 19 pandemic) have been more devastating and have contributed to significant worldwide mortality in pandemics (Ye et al., 2020). Accounting for more than 672,000,000 infected individuals and 6,740,000 associated deaths worldwide, the rapid spread of COVID- 19 is a considerable burden and threat to public health and safety (Worldometer, 2023). The etiological agent responsible for this disastrous episode is known as SARS- CoV- 2 (WHO, 2021). Akin to the previous SARS- CoV and MERS- CoV, the SARS- CoV- 2 falls under the beta- coronavirus genera. Notably, the estimated fatality rate of SARS- CoV- 2 is much lower at 3.4% compared to 9.6% and 40% for SARS- CoV and MERS- CoV, respectively (Peiris et al., 2003; Zumla, Hui & Perlman, 2015). Despite this, the high infection rate of SARS- CoV- 2 overwhelmingly surpasses both SARS- CoV and MERS- CoV, leading to the rapid progression of infection in individuals and the spatial range of epidemic regions (Zheng, 2020). What is even more alarming is that with rapid replication of the SARS- CoV- 2 virus in humans, we are witnessing a vast number of new variants of this virus during this pandemic.

As a zoonotic virus, coronaviruses are often associated with animal reservoirs. Several animals, such as bats, can travel long distances and congregate within the community, resulting in the high occurrence of animal- human interspecies barrier crossing, increasing the occurrence of zoonotic transmission of coronaviruses and species spillover events (Wong et al., 2019). The previous SARS- CoV and MERS- CoV are examples of such circumstances. As such, the SARS- CoV and MERS- CoV are believed to be associated with bat and dromedary camels, respectively. In contrast, the
origin of SARS- CoV- 2 remains debatable, with evidence pointing towards bats as the natural reservoir (Andersen et al., 2020). Similar to its counterparts, the common symptoms of SARS- CoV- 2 include fever, dry cough, headache, fatigue, pneumonia, and dyspnoea (Zhou et al., 2020). Less common symptoms such as loss of taste or smell, nasal congestion, diarrhoea, gastrointestinal distress, muscle weakness and rashes are also reported (WHO, 2021).

In this urgent time of need and the emergence of new variants, antiviral drug repositioning is a feasible approach in addition to vaccine development and the discovery of new antiviral compounds. In the quest for effective antiviral therapy against SARS- CoV- 2, numerous drug candidates have been studied for drug repositioning potentials, such as remdesivir, molnupiravir, ivermectin and oseltamivir, to name a few (Yip et al., 2022). Moreover, many studies have revealed plausible targets for drug inhibitors, such as the RdRp protein complex, in hopes of inhibiting the viral replication of SARS- CoV- 2 (Low, Yip & Lal, 2022). Given the rapid development of COVID- 19 and its emerging variants, it is essential to revisit and understand the past and present coronavirus outbreaks in humans. We all understand that viral evolution towards new variants will undoubtedly decrease the efficacies of existing vaccines, but this will be a constant and ongoing task where antiviral drugs targeting internal proteins of the virus, rather than surface (spike) proteins may become a better alternative, in the long run. This chapter aims to provide consolidated information concerning SARS- CoV- 2 and its emerging variants. We describe the molecular biology of transmission and replication, thereby highlighting the distinctions between the newly emerging variants.

Springer, Singapore, 2024

Cancer is a diverse group of diseases predominantly characterized by uncontrolled cellular prolif... more Cancer is a diverse group of diseases predominantly characterized by uncontrolled cellular proliferation. Tumour cells can invade healthy tissues and, in severe cases, metastasize, leading to an overall decline in an individual's health. Mutations in regulatory genes are often the source of shifts in cellular functions, leading to a cascade of mis-modulations in cellular pathways. Often, it is difficult to thoroughly determine the exact mechanisms which cause cancer. Yet, some cellular markers are more significant than others which can lead research a step closer to the determination of novel biomarkers and therapeutic targets. The human polyadenylate binding protein (PABPC1) is an RNA-binding protein known for its roles in mRNA metabolism, export and translation. In recent studies, many have found that PABPC1 plays an important regulatory role in diverse cancers, including breast, lung, gastric, liver, colorectal, oesophageal, prostate, bladder and brain cancers. In this chapter, we summarized the findings of the most recent studies that reported the roles of human PABPC1 in these cancers to highlight the potential of PABPC1 as a future therapeutic and diagnostic target for cancers.