Before Saying Farewell to Hydroxychloroquine Usage in Practice: Evaluation of Our Safety Data on Hydroxychloroquine Treatment in Children with COVID-19

Objective:This study aimed to evaluate the adverse effects of hydroxy-chloroquine (HCQ) in children with COVID-19. Material and Methods: This study was conducted between March -August 2020 at a referral tertiary hospital for pediatric infectious diseases in the Aegean Region of Turkey. All hospitalized children with COVID-19 who were received HCQ include in this study. An electrocardiogram (ECG) was performed prior to the initiation of HCQ and at certain times (first and 24th hours of HCQ administration and two hours after the final dose of HCQ) during treatment. Adverse effects associated with HCQ were evaluated during the hospitalization and also the first and second months after discharge. Results: A total of 62 children with COVID-19 who administered HCQ treatment were evaluated. Of these, 35 (56.5%) were girls and 27 (43.5%) were boys. The mean age 13.7 +/- 3.0 years (range 6.0 to 18.0 years). Prior to the admission, none of the patients had arrhythmia, cardiovascular disease, or any cardiotoxic drugs usage. There was no abnormality on the baseline and following ECGs during the treatment with HCQ. Thir-teen patients had nausea (20.9%) and 10 patients (17.7%) had mild ab-dominal pain. None of the patients had no arrhythmia. Conclusion: No cardiac side effects were observed in our patients. How-ever, it is not possible to give a general statement on the safety data of HCQ therapy without any randomized controlled large-scale studies.

Impact of Drug Repurposing on SARS-Cov-2 Main Protease

Abstract: The recent emergence of the severe acute respiratory disease caused by a novel coronavirus remains a concern posing many challenges to public health and the global economy. The resolved crystal structure of the main protease of SARS-CoV-2 or SCV2 (Mpro) has led to its identification as an attractive target for designing potent antiviral drugs. Herein, we provide a comparative molecular impact of hydroxychloroquine (HCQ), remdesivir, and β-D-N4-Hydroxycytidine (NHC) binding on SCV2 Mpro using various computational approaches like molecular docking and molecular dynamics (MD) simulation. Data analyses showed that HCQ, remdesivir, and NHC binding to SARS-CoV-2 Mpro decrease the protease loop capacity to fluctuate. These binding influences the drugs' optimum orientation in the conformational space of SCV2 Mpro and produce noticeable steric effects on the interactive residues. An increased hydrogen bond formation was observed in SCV2 Mpro–NHC complex with a decreased receptor residence time during NHC binding. The binding mode of remdesivir to SCV2 Mpro differs from other drugs having van der Waals interaction as the force stabilizing protein–remdesivir complex. Electrostatic interaction dominates in the SCV2 Mpro−HCQ and SCV2 Mpro–NHC. Residue Glu166 was highly involved in the stability of remdesivir and NHC binding at the SCV2 Mpro active site, while Asp187 provides stability for HCQ binding. © 2022, Pleiades Publishing, Ltd.

Kinetic Studies for the Release of Hydroxychloroquine Sulphate Drug (HCQ) In-vitro in Simulated Gastric and Intestinal Medium from Sodium Alginate and Lignosulphonic Acid Blends

Biodegradable polymeric blends are used to study the controlled release of Hydroxychloroquine sulphate (HCQ) as the model drug used extensively in COVID-19 treatments. HCQ drug is loaded in sodium alginate (NaAlg) and lignosulphonic acid (NaLS) blends as matrix are crosslinked using calcium chloride solution. Its release is evaluated in different pH mediums of simulated gastric fluid (SGF) and simulated intestinal fluid (SIF). The HCQ release data obtained during experimentation is used to study kinetics using different models to investigate polymeric relaxation's drug diffusion and mechanism in water-soluble HCQ drug. The drug release mechanism best fits the Higuchi model with Fickian diffusion as the primary polymeric relaxation mechanism. © 2023, Walailak University. All rights reserved.

Hydroxychloroquine Sulfate (Plaquenil): A Possible Candidate for Pandemic SARS-CoV-2 or (COVID-19)?

Hydroxychloroquine is a chloroquine derivative recognized for treating 'SARS-CoV-2 or COVID-19', among its other uses. It is one of the key drugs used for the treatment of malaria and other respiratory diseases. The drug exhibits multiple pharmacological activities such as anti-malarial, antidiabetic, anticancer, anti-HIV, antifungal, antimicrobial, and antioxidant activities. The coronavirus has recently shown five mutations or genetic change in its structure due to change in the climatic condition (i.e. R207C (nsp 2-27) - Wuhan (China), V378 I (nsp 2-198) - Italy, M2796I (nsp 4-33) - Iran, L3606F (nsp 6-37)-America and V9082F (ORF 7a-74) - Kuwait). There are many preclinical, clinical, theoretical, and experimental evidences that support the effectiveness of HCQ and CQ on patients affected by COVID-19. Based on the evidence currently underway and future research, we will be able to provide better analysis of the role of HCQ and CQ in the COVID-19 transition. It displays several activities related to the respiratory system, and numerous studies have suggested that the compound may be beneficial in protection against diseases such as malaria and lupus erythematosus. The present review represents the role and use of HCQ in the COVID-19 dis-ease. The object of this review study is based on the research evidence obtained from different au-thentic sources. It is currently used in the study of HCQ and CQ for the treatment of coronavirus and various other infections.Copyright © 2021 Bentham Science Publishers.

Biomarkers of COVID-19 and technologies to combat SARS-CoV-2.

Due to the unprecedented public health crisis caused by COVID-19, our first contribution to the newly launching journal, Advances in Biomarker Sciences and Technology, has abruptly diverted to focus on the current pandemic. As the number of new COVID-19 cases and deaths continue to rise steadily around the world, the common goal of healthcare providers, scientists, and government officials worldwide has been to identify the best way to detect the novel coronavirus, named SARS-CoV-2, and to treat the viral infection - COVID-19. Accurate detection, timely diagnosis, effective treatment, and future prevention are the vital keys to management of COVID-19, and can help curb the viral spread. Traditionally, biomarkers play a pivotal role in the early detection of disease etiology, diagnosis, treatment and prognosis. To assist myriad ongoing investigations and innovations, we developed this current article to overview known and emerging biomarkers for SARS-CoV-2 detection, COVID-19 diagnostics, treatment and prognosis, and ongoing work to identify and develop more biomarkers for new drugs and vaccines. Moreover, biomarkers of socio-psychological stress, the high-technology quest for new virtual drug screening, and digital applications are described.

A Narrative Review of Emerging Therapeutics for COVID-19.

The novel severe acute respiratory syndrome coronavirus 2, the causal agent of coronavirus disease 2019 (COVID-19), quickly spread around the world, resulting in the most aggressive pandemic experienced in more than 100 years. Research on targeted therapies and vaccines has been initiated on an unprecedented scale and speed but will take months and even years to come to fruition. Meanwhile, the efficacy of emerging therapeutics for use in treating COVID-19 is feverishly being investigated to identify the best available treatment options for dealing with the current wave of disease. This review of publications with a "treatment" tag through June 29, 2020 in the National Library of Medicine's LitCovid literature hub, provides frontline clinicians with a pragmatic summary of the current state of the rapidly evolving evidence supporting emerging candidate therapeutics for COVID-19. Two main categories of pharmaceutical therapeutics are showing promise: those with antiviral activity directly addressing infection and those that counteract the inflammatory cytokine storm induced by severe disease. Preliminary results suggest that other approaches such as convalescent plasma therapy and lung radiation therapy may have some efficacy. The current clinical evidence for potential treatments is preliminary-often small retrospective series or early results of randomized trials-and the science is evolving rapidly. The long-term results from large, well-designed randomized controlled trials will provide definitive evidence for therapeutic effectiveness and are likely months away. The trial landscape for promising therapies is described.

Application of the PHENotype SIMulator for rapid identification of potential candidates in effective COVID-19 drug repurposing.

The current, rapidly diversifying pandemic has accelerated the need for efficient and effective identification of potential drug candidates for COVID-19. Knowledge on host-immune response to SARS-CoV-2 infection, however, remains limited with few drugs approved to date. Viable strategies and tools are rapidly arising to address this, especially with repurposing of existing drugs offering significant promise. Here we introduce a systems biology tool, the PHENotype SIMulator, which -by leveraging available transcriptomic and proteomic databases-allows modeling of SARS-CoV-2 infection in host cells in silico to i) determine with high sensitivity and specificity (both>96%) the viral effects on cellular host-immune response, resulting in specific cellular SARS-CoV-2 signatures and ii) utilize these cell-specific signatures to identify promising repurposable therapeutics. Powered by this tool, coupled with domain expertise, we identify several potential COVID-19 drugs including methylprednisolone and metformin, and further discern key cellular SARS-CoV-2-affected pathways as potential druggable targets in COVID-19 pathogenesis.

Impact of COVID-19 pandemic on medicine supply chain for patients with chronic diseases: Experiences of the community pharmacists.

Problem considered: Coronavirus disease(COVID-19) outbroke towards the end of December 2019 in China, soon it started spreading rapidly to various countries leading to an outburst of pandemic. Due to the restrictions imposed to control the spread of the infection, globally the manufacturing, import and export of medicine and the healthcare services to patients with chronic illness had been affected. This study aimed to explore the perspectives of the pharmacists on the medicine supply chain for patients with chronic diseases during COVID-19 pandemic in India. Methods: This study is a prospective, qualitative research involving telephonic, semi-structured in-depth interviews. An interview guide for pharmacists was prepared and validated using "Interview Protocol Refinement" method. Purposive sampling method was used to recruit the pharmacists; a telephonic oral consent was obtained. The interview session was audio recorded and the recordings were transcribed verbatim. Further, transcripts were validated and later analysed using NVivo software. Results: A total of 8 participants were interviewed during our study. Thematic analysis of the transcripts resulted in seven main themes. The study showed that there was deficiency in medicine supply during the COVID-19 pandemic and the pharmacists faced several challenges in procuring and storing the medication, arranging for unavailable medicines, medication dispensing and provision of the services such as medicine delivery, patient counselling. There was also scarcity of manpower leading to extra workload and working overtime. Conclusion: Uninterrupted supply of essential medicine is the backbone of health care system. An effective plan and appropriate strategies are vital to combat such future emergencies.

An observational multi-centric COVID-19 sequelae study among health care workers.

Background: India has seen more than 43 million confirmed cases of COVID-19 as of April 2022, with a recovery rate of 98.8%, resulting in a large section of the population including the healthcare workers (HCWs), susceptible to develop post COVID sequelae. This study was carried out to assess the nature and prevalence of medical sequelae following COVID-19 infection, and risk factors, if any. Methods: This was an observational, multicenter cross-sectional study conducted at eight tertiary care centers. The consenting participants were HCWs between 12 and 52 weeks post discharge after COVID-19 infection. Data on demographics, medical history, clinical features of COVID-19 and various symptoms of COVID sequelae was collected through specific questionnaire. Finding: Mean age of the 679 eligible participants was 31.49 ± 9.54 years. The overall prevalence of COVID sequelae was 30.34%, with fatigue (11.5%) being the most common followed by insomnia (8.5%), difficulty in breathing during activity (6%) and pain in joints (5%). The odds of having any sequelae were significantly higher among participants who had moderate to severe COVID-19 (OR 6.51; 95% CI 3.46-12.23) and lower among males (OR 0.55; 95% CI 0.39-0.76). Besides these, other predictors for having sequelae were age (≥45 years), presence of any comorbidity (especially hypertension and asthma), category of HCW (non-doctors vs doctors) and hospitalisation due to COVID-19. Interpretation: Approximately one-third of the participants experienced COVID sequelae. Severity of COVID illness, female gender, advanced age, co-morbidity were significant risk factors for COVID sequelae. Funding: This work is a part of Indian Council for Medical Research (ICMR)- Rational Use of Medicines network. No additional financial support was received from ICMR to carry out the work, for study materials, medical writing, and APC.

Hydroxychloroquine Mitigates Dilated Cardiomyopathy Phenotype in Transgenic D94A Mice.

In this study, we aimed to investigate whether short-term and low-dose treatment with hydroxychloroquine (HCQ), an antimalarial drug, can modulate heart function in a preclinical model of dilated cardiomyopathy (DCM) expressing the D94A mutation in cardiac myosin regulatory light chain (RLC) compared with healthy non-transgenic (NTg) littermates. Increased interest in HCQ came with the COVID-19 pandemic, but the risk of cardiotoxic side effects of HCQ raised concerns, especially in patients with an underlying heart condition, e.g., cardiomyopathy. Effects of HCQ treatment vs. placebo (H2O), administered in Tg-D94A vs. NTg mice over one month, were studied by echocardiography and muscle contractile mechanics. Global longitudinal strain analysis showed the HCQ-mediated improvement in heart performance in DCM mice. At the molecular level, HCQ promoted the switch from myosin's super-relaxed (SRX) to disordered relaxed (DRX) state in DCM-D94A hearts. This result indicated more myosin cross-bridges exiting a hypocontractile SRX-OFF state and assuming the DRX-ON state, thus potentially enhancing myosin motor function in DCM mice. This bottom-up investigation of the pharmacological use of HCQ at the level of myosin molecules, muscle fibers, and whole hearts provides novel insights into mechanisms by which HCQ therapy mitigates some abnormal phenotypes in DCM-D94A mice and causes no harm in healthy NTg hearts.

Role of Tocilizumab in Fighting COVID-19

Background: Tocilizumab is the repurposed drug used in the severely ill COVID-19 patients. A lot of traction has gain over the drug but more studies are awaited to ensure the efficacy of the drug with proper backing from empirical data. Tocilizumab, a drug which is used in treatment of rheumatoid arthritis suddenly came into limelight when it got listed as drugs used for the treatment of COVID-19 patients. As earlier discussed, many existing drugs which were already in use for treating other ailments were being tested if they are suitable to treat COVID-19 disease. Tocilizumab have the anti-inflammatory properties which were in particular were useful in COVID-19 which creates an inflammation all across the organs. Summary: COVID-19 is the novel disease outbreak later progressed into deadly pandemic has presented the huge challenge to contain it clinically as no drug was available prior the outbreak of the disease. Vast amount of drugs can be used to at least suppress the viral spread which was found to be true. Although it was not hundred percent foolproof but it was an emergency situation and various drugs were used according to local ground conditions and patients response to the drug along with age and severity of the illness. Tocilizumab was one such drug which was repurposed for the treatment of COVID-19 patients. Many drugs such as Hydroxycholoroquine (HCQ), Tocilizumab were repurposed from their existing use. Tocilizumab is currently used in the treatment of rheumatoid arthritis. Various studies have shown the efficacy of the drug among the severely ill COVID-19 patients which ranges up to 66 percent. In certain cases worsening of the existing medical condition has been observed. Conclusion: Vaccine nationalism must be set aside and low and middle income countries where most of the population of the world resides, should be vaccinated as even one case can culminate into another disaster as was seen during highly contagious COVID-19. More empirical data is needed from across the globe to ensure the assessment of the efficacy of the drug. Also certain cases of shortage of the said drug for non-COVID-19 purpose also looked into seriously has it can create a parallel disaster.

ZnO-chlorogenic acid nanostructured complex inhibits Covid-19 pathogenesis and increases hydroxychloroquine efficacy.

Objective: The study purpose was to compare the anti- novel coronavirus disease 2019 (COVID-19) property of chlorogenic acid (CGA) and Zinc oxide nanoparticles (ZnO-NP) with the new valid synthesized complex of ZnO /CGA-NPs. Methods: The facile mixing method was utilized to prepare ZnO/CGA-NPs. The in vitro effect of different ZnO/CGA-NPs concentrations on papain-like protease (PLpro) and spike protein- receptor-binding domain (RBD) was measured by ELISA technique. The compounds effects on SARS-CoV2 were determined on viral entry, replication, and assembly by using plaque reduction assay, qPCR, and ELISA techniques. Their individual effects or mixed with hydroxychloroquine (HCQ) on erythrocytes (RBCs) and leukocytes (WBCs) were evaluated by routine cell culture technique. Finally, turbidity and agar well diffusion assays were done to evaluate their antimicrobial properties against Escherichia. coli, klebsila pneumonia, Streptococcus pyogenes, Staphylococcus aureus, and Candida albicans. Results: The results confirmed that the uniformly dispersed ZnO-NPs were converted to aggregated form of ZnO/CGA-NPs upon the addition of CGA. The inhibitory concentration 50 (IC50) of ZnO /CGA-NPs against RBD, angiotensin-converting enzyme 2 (ACE2) and PLpro were 1647.7, 323.3 µg/mL and 38.7 µg/mL, respectively. Also, it inhibited E-gene, RdRp gene, E-protein, and spike protein with an IC50 of 0.11, 0.13, 0.48, and 0.37 µg/mL, respectively. It acted as an antimicrobial against all tested organisms with a minimum inhibitory concentration (MIC) of 26 µg/mL. Finally, ZnO/CGA-NPs Complex (0.1 IC50) prevented the cytotoxic effect of HCQ on RBCs and WBC by 92.3 and 90 %, respectively. Conclusion: ZnO/CGA-NPs Complex can be considered as a new anti- severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) compound.

A review of the effects of ATP and hydroxychloroquine on the phase separation of the SARS-CoV-2 nucleocapsid protein.

SARS-CoV-2 is the coronavirus causing the ongoing pandemic with > 460 millions of infections and > 6 millions of deaths. SARS-CoV-2 nucleocapsid (N) is the only structural protein which plays essential roles in almost all key steps of the viral life cycle with its diverse functions depending on liquid-liquid phase separation (LLPS) driven by interacting with various nucleic acids. The 419-residue N protein is highly conserved in all variants including delta and omicron, and composed of both folded N-/C-terminal domains (NTD/CTD) as well as three long intrinsically disordered regions (IDRs). Recent results have suggested that its CTD and IDRs are also cryptic nucleic acid-binding domains. In this context, any small molecules capable of interfering in its interaction with nucleic acids are anticipated to modulate its LLPS and associated functions. Indeed, ATP, the energy currency existing at very high concentrations (2-12 mM) in all living cells but absent in viruses, modulates LLPS of N protein, and consequently appears to be evolutionarily hijacked by SARS-CoV-2 to promote its life cycle. Hydroxychloroquine (HCQ) has been also shown to specifically bind NTD and CTD to inhibit their interactions with nucleic acids, as well as to disrupt LLPS. Particularly, the unique structure of the HCQ-CTD complex offers a promising strategy for further design of anti-SARS-CoV-2 drugs with better affinity and specificity. The finding may indicate that LLPS is indeed druggable by small molecules, thus opening up a promising direction for drug discovery/design by targeting LLPS in general.

Consumption Trends of Antibiotics in Brazil During the COVID-19 Pandemic.

Background: In 2019, a new type of coronavirus emerged and spread to the rest of the world. Numerous drugs were identified as possible treatments. Among the candidates for possible treatment was azithromycin alone or in combination with other drugs. As a result, many clinicians in Brazil have prescribed azithromycin in an attempt to combat or minimize the effects of COVID19. Aim: This study analyzed the sales data of the main antibiotics prescribed in Brazil to verify the change in consumption trends of these drugs during the COVID-19 pandemic. Methods: This is an interrupted time series that analyzed antimicrobial sales data between January 2014 and July 2021, publicly accessible information obtained from the Brazilian government's website. Monthly means of "defined daily doses of DDDs" (DDDs per 1,000 inhabitants per day) of antibiotics were compared by analysis of variance, followed by the Dunnett Multiple Comparisons Test. Monthly trend changes in antibiotic use were verified using Joinpoint regression. Results: Amoxicillin (31.97%), azithromycin (18.33%), and cefalexin (16.61%) were the most sold antibiotics in Brazil during the evaluation period. Azithromycin consumption rose from 1.40 DDDs in February 2020 to 3.53 DDDs in July 2020. Azithromycin sales showed a significant increase in the pandemic period [Monthly Percent Change (MPC) 5.83%, 95% 1.80; 10.00], whereas there was a fall in amoxicillin sales (MPC -9.00%, 95% CI -14.70; -2.90) and cefalexin [MPC-2.70%, 95% (CI -6.30; -1.10)] in this same period. Conclusion: The COVID-19 pandemic changed the pattern of antibiotic consumption in Brazil, with a decrease in the use of amoxicillin and cefalexin and an increase in the consumption of azithromycin.

The Impact of COVID-19 On Comorbidities: A Review Of Recent Updates For Combating It.

Coronavirus disease is caused by the SARS-CoV-2 virus. The virus first appeared in Wuhan (China) in December 2019 and has spread globally. Till now, it affected 269 million people with 5.3 million deaths in 224 countries and territories. With the emergence of variants like Omicron, the COVID-19 cases grew exponentially, with thousands of deaths. The general symptoms of COVID-19 include fever, sore throat, cough, lung infections, and, in severe cases, acute respiratory distress syndrome, sepsis, and death. SARS-CoV-2 predominantly affects the lung, but it can also affect other organs such as the brain, heart, and gastrointestinal system. It is observed that 75 % of hospitalized COVID-19 patients have at least one COVID-19 associated comorbidity. The most common reported comorbidities are hypertension, NDs, diabetes, cancer, endothelial dysfunction, and CVDs. Moreover, older and pre-existing polypharmacy patients have worsened COVID-19 associated complications. SARS-CoV-2 also results in the hypercoagulability issues like gangrene, stroke, pulmonary embolism, and other associated complications. This review aims to provide the latest information on the impact of the COVID-19 on pre-existing comorbidities such as CVDs, NDs, COPD, and other complications. This review will help us to understand the current scenario of COVID-19 and comorbidities; thus, it will play an important role in the management and decision-making efforts to tackle such complications.

Hydroxychloroquine: Adverse Drug Reaction Profile of an Old Drug in a New Situation.

BACKGROUND: Hydroxychloroquine (HCQ) has been extensively used during the COVID-19 pandemic both as a therapeutic and prophylactic drug. HCQ is generally well tolerated; however, adverse drug reactions (ADRs) in COVID-19 need further exploration. In this study, we have determined the type and pattern of ADRs of HCQ as a prophylactic and therapeutic drug in COVID-19. METHODS: All spontaneous suspected ADR reports due to HCQ in COVID-19 patients submitted to the ADR monitoring of a tertiary care hospital were included. Additionally, a survey was designed for active surveillance of ADRs among healthcare professionals (HCPs) who were on prophylaxis with HCQ. The ADRs were analyzed to determine severity, causality, and preventability using the Hartwig Scale, World Health Organisation-Uppasala Monitoring Centre (WHO-UMC) scale, and modified Schumock and Thornton criterion respectively. RESULTS: Sixty-four ADR reports were received from COVID-19 patients. A total of 78 ADRs were reported by 49 HCPs who were on HCQ prophylaxis. The majority of the patients had ADRs related to skin and soft tissues (37.5%), whereas the HCPs on prophylaxis mostly had gastrointestinal complaints (42.3%). ADRs observed in HCPs on prophylaxis were mild, not requiring any intervention. However, 50% of ADRs in patients were of "moderate" category. CONCLUSION: Undiscerning and unsupervised use of HCQ can expose the general population as well as patients to serious adverse drug effects. Utmost care is necessary before using HCQ prophylactically or for treatment in COVID-19.

Hydroxychloroquine (HCQ) and its Synthetic Precursors: A Review

Hydroxychloroquine (HCQ) is an extremely important drug used for the treatment of various ailments. WHO listed it as one of the essential drugs. The utility of hydroxychloroquine (HCQ) as prophylaxis of COVID19, although debated, is well known. We have reviewed synthetic strategies for the industrial and academic synthesis of HCQ and its key intermediates like 4,7-dichloroquinoline (4,7-DCQ) and 2-((4-aminopentyl)(ethyl)amino)ethan-1-ol 9 (aka hydroxy novaldiamine;HNDA). The review is expected to provide the right perspective of state-of-the-art knowledge in this field so that further developments are possible. © 2022 Bentham Science Publishers.

Original The role of hydroxychloroquine in high-risk individuals with coronavirus disease (COVID-19)

Objective: This study aimed to compare the symptoms and the severity of the illness among positive Coronavirus Disease 2019 (COVID-19) high-risk individuals with or without the prophylactic use of hydroxychlo-roquine (HCQ). Methods: This cross-sectional study was conducted at the Pakistan Institute of Medical Sciences (PIMS), Islamabad. A total of 485 high-risk individuals with possible exposure to COVID-19 were enrolled in the study. The data were collected through a pre-designed self-repor ting questionnaire inquiring about the individual's history, baseline characteristics, COVID-19 associated risk factors, exposure history, polymerase chain reaction (PCR) and antibody screening results, HCQ drug dosage, and adverse effects. The COVID-19 symptoms and the severity of the illness were also recorded. The individuals were divided into two groups as per the HCQ intake, i.e. users and non-users, and compared for statistical significance. The data of 121 PCR positive COVID-19 individuals were also compared between the two groups. Results: Out of 485 individuals, 264 (54.4%) were HCQ users. All the study demographics were comparable in both study groups. The study revealed that the COVID-19 positive cases were significantly less reported in the HCQ user group than in the non-HCQ user group (40.3% vs. 58.5%;P-value = 0.004). Of these 121 COVID-19 positive cases, shortness of breath (11.6%), anosmia (13%) and the severity of the illness requiring hospitalization (14.5%) were profound among non-HCQ users as compared to those who were prophylactically receiving HCQ. No serious side-effects were reported by the HCQ users. Conclusion: Voluntary pre-exposure HCQ administration significantly reduces the severity of illness, both symptomatic and radiological, among COVID-19 positive individuals.

Structural basis of anti-SARS-CoV-2 activity of HCQ: Specific binding to N protein to disrupt its interaction with nucleic acids and LLPS

SARS-CoV-2 nucleocapsid (N) protein plays the essential roles in key steps of the viral life cycle, thus representing a top drug target. Functionality of N protein including liquid-liquid phase separation (LLPS) depends on its interaction with nucleic acids. Only the variants with N proteins functional in binding nucleic acids might survive and spread in evolution and indeed, the residues critical for binding nucleic acids are highly conserved. Hydroxychloroquine (HCQ) was shown to prevent the transmission in a large-scale clinical study in Singapore but so far, no specific SARS-CoV-2 protein was experimentally identified to be targeted by HCQ. Here by NMR, we unambiguously decode that HCQ specifically binds NTD and CTD of N protein with Kd of 112.1 and 57.1 ?M respectively to inhibit their interaction with nucleic acid, as well as to disrupt LLPS. Most importantly, HCQ-binding residues are identical in SARS-CoV-2 variants and therefore HCQ is likely effective to different variants. The results not only provide a structural basis for the anti-SARS-CoV-2 activity of HCQ, but also renders HCQ to be the first known drug capable of targeting LLPS. Furthermore, the unique structure of the HCQ-CTD complex suggests a promising strategy for design of better anti-SARS-CoV-2 drugs from HCQ. Copyright © 2021 The Author(s). Published by Cambridge University Press.