Since there is no vaccine or regulatory approved therapy available for treatment of SARS-CoV-2 infection, the medical need to prevent the transition of a mild into the severe COVID-19 stage of infection is of outmost importance. Among several drug candidates, Chloroquine (CQN) and Hydroxy-Chloroquine (H-CQN) have been tested most intensively. However, the therapeutic effect of H-CQN and CQN has been discussed controversially in the light of severe side effects. Originally, H-CQN descended from the natural substance Quinine, a medicinal product used since the Middle Ages and is now regulatory approved for various indications. We hypothesized that Quinine also exerts anti-SARS-CoV-2 activity. First, virus production in Vero B4 cells was analyzed by Western blot, showing that Quinine exerts antiviral activity against SARS-CoV-2 that at 10 µM was even stronger than that of H-CQN or CQN. Second, fluorescence end-point and time lapse analysis of SARS-CoV-2-mNeonGreen-infected Caco-2 cells could confirm a similar antiviral effect of Quinine in a human-derived cell line. Thereby, our in vitro studies revealed, that the antiviral effect appears to be specific, since in Vero cells Quinine impacted cell viability at approximately 50-fold higher concentration, while the therapeutic window of H-CQN and CQN was approximately 10-fold lower. In Caco-2 cells no toxic effect was observed while complete block of infection occurred between 50 and 100 µM at high MOIs. In conclusion, our data indicate that Quinine would have the potential of a well tolerable and widely used treatment option for SARS-CoV-2 infections, with a predictable and significantly better toxicological profile when compared to H-CQN or CQN.

(1) Background: Plasmodium vivax causes the largest malaria burden in Brazil, and chloroquine resistance poses a challenge to eliminating malaria by 2035. Illegal mining in the Roraima Yanomami indigenous territory can lead to the introduction of resistant parasites. This study aimed to investigate mutations in the pvcrt-o and pvmdr-1 genes to determine their potential as predictors of P. vivax chloroquine-resistant phenotypes. (2) Methods: Samples were collected in two health centers of Boa Vista. A questionnaire was completed, and blood was drawn from each patient. Then, DNA extraction, PCR, amplicon purification, and DNA sequencing were performed. After alignment with the Sal-1, the amplified fragment was analyzed. Patients infected with the mutant parasites were queried in the Surveillance Information System. (3) Results: 98% (157/164) of participants were from illegal mining areas. The pvcrt-o was sequenced in 151 samples, and the K10 insertion was identified in 13% of them. The pvmdr1 was sequenced in 80 samples: the MYF haplotype (958M) was detected in 92% of them, the TYF in 8%, while MYL was absent. No cases of recrudescence, hospitalization, or death were found. (4) Conclusions: Mutations in the pvcrt-o and pvmdr-1 genes have no potential to predict chloroquine resistance in P. vivax.

The COVID-19 pandemic is one of the largest challenges in medicine and health care worldwide in recent decades, and it is infecting and killing increasing numbers of people every day. In this paper, we discuss the possible relationships among lysosomotropism, increasing lysosomal pH, and the SARS-CoV-2 infection and disease process, and we deduce a possible approach for treatment and prophylaxis. Lysosomotropism is a biological characteristic of small molecules, such as (hydroxyl)chloroquine, amitriptyline, NB 06, or sertraline, which is present in addition to intrinsic receptor-mediated or enzymatic pharmacological effects. Lysosomotropic compounds affect prominent inflammatory messengers, such as IL1B, CCL4, CCL20, and IL6, as well as cathepsin L dependent viral entry (fusion) into host cells. Therefore, this heterogeneous group of compounds is a promising candidate for the prevention and treatment of SARS-CoV-2 infections, as well as influenza A infections and cytokine release syndrome (CRS) triggered by bacterial or viral infections. Patients who have already taken medications with lysosomotropic compounds for other pre-existing conditions may benefit from this treatment in the COVID-19 pandemic. Increased lysosomal pH levels play an important role in the disease process in common skin disorders, such as psoriasis and atopic dermatitis, thus suggesting that affected individuals might benefit from their particular conditions in the COVID-19 pandemic. We suggest data analysis of patients with these diseases, and who are treated with lysosomotropic compounds, and, if the results are promising, subsequent clinical testing of off-label therapy with clinically approved lysosomotropic compounds in the current COVID-19 pandemic and future influenza A pandemics.

The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2, has been declared by the World Health Organization (WHO) as a pandemic. Unfortunately, finding a vaccine or developing drugs from the scratch is a time-consuming luxury given the widespread and high fatality rates of the virus. In the short term, repurposing of drugs already in use seem to be the most rational step to quickly and effectively curb the virus. Several antiviral agents had been proposed as possible remedies, but the 4-aminoquinolines, Chloroquine (CHQ) and hydroxychloroquine (HCHQ) appear to be generating more interest. They are generic, cheaply available and have proven efficacy against malaria parasites in Africa. The human immunodeficiency virus (HIV), on the other hand, targets the immune system thereby reducing the patient’s ability to fight infections. Sadly, 68% of the global HIV burden occur in Africa. It is therefore anticipated that incidence of severe forms of COVID-19 could occur in Africa because of associated endemic conditions that compromise the immune system. With CHQ and HCHQ being considered for clinical use against COVID-19, there is a need to highlight their potential merits and confounding variables in the subgroup of patients with or without HIV.

Quinine and its less toxic derivatives have served humanity for decades as potent antimalarial drugs. Emergence of drug resistance has narrowed the usage of these drugs in malaria prevention and treatment. Fortunately, these drugs have roles in the treatment of other diseases as well including rheumatic disorders and viral infections. Quinine derivatives have proven antiviral effects, especially against human immunodeficiency virus (HIV), Zika virus (ZiKV), herpes simplex virus (HSV), Ebola virus and dengue virus (DENV). The prophylactic and therapeutic role of Chloroquine/hydroxychroquine has become a topic of interest after the recent outbreak of novel Corona virus-19 (nCoV-19). This virus is also named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and WHO has officially named this disease as Corona virus disease 2019 (COVID-19). This lethal virus has affected almost 186 countries of the world till to date just in a period of four months of its outbreak. No approved antiviral drug is existed for the treatment of COVID-19. Therefore, this review is focused on potential prophylactic and therapeutic role of chloroquine/hydroxychlroquine for COVID-19.

World is currently experiencing a new pandemic for which no curative treatment is available. At this time, coronavirus disease 2019 (Covid-19) has reached 183 countries and has caused several deaths. Many reports presented chloroquine (CQ) and hydrochloroquine (HCQ), former drugs used against malaria, as the best current choice to fight this terrible disease. As these molecules had been withdrawn in malaria treatment policy due to chemoresistance, their reintroduction could have some consequences. Though local malaria prevalence could decrease for a while, molecular changes are likely to happen on some plasmodium falciparum genes involved in conferring drug resistance. This could threaten efforts in malaria control, if these molecules are widely administered.

The novel coronavirus 2019 (COVID-19) pandemic is rapidly advancing despite public health measures. Pharmaceutical prophylaxis is an established approach to potentially control infectious diseases and is one solution to the urgent public health challenge posed by COVID-19. Screening and development of new vaccines and antivirals is expensive and time consuming while the repositioning of available drugs should receive priority attention as well as international government and agency support. Here we propose an old drug chloroquine (CQ) to be urgently repositioned as an ideal antiviral prophylactic against COVID-19. CQ has ability to block viral attachment and entry to host cells. Its proven clinical efficacy against a variety of viruses including COVID-19 and its current deployment in COVID-19 therapeutic trials strengthens its potential candidacy as a prophylactic. Furthermore, CQ has a long safety record, is inexpensive and widely available. Here we reviewed CQ's antiviral mechanisms, its laboratory efficacy activity against COVID-19, as well as CQ's pharmacokinetics in its established use against malaria and autoimmune diseases to recommend safe and potentially efficacious dose regimens for protection against COVID-19: a pre-exposure prophylaxis of 250-500mg daily and post-exposure prophylaxis at 8mg/kg/day for 3 days. We recommend further urgent research on CQ for COVID-19 prevention and urge that the above regimens be investigated in parallel with mass deployment by relevant agencies in attempts to contain the pandemic without unnecessary regulatory delays as benefits far outweigh risks or costs.

The replacement of chloroquine with artemisinin-based combination therapies (ACTs) for over a decade has had varying impacts on the ability of malaria parasite to sustain its chloroquine resistance prowess in different malaria-endemic regions. We evaluated the frequency of Plasmodium falciparum chloroquine resistance transporter (PfCRT) mutations in an endemic area of southwest Nigeria 17 years after replacement of chloroquine with ACTs for malaria treatment. Genomic DNA was isolated from dried blood spot samples obtained from 129 patients (aged 1-35 years) with microscopically confirmed P. falciparum infection. PfCRT fragments covering codons 72-76, CVMNK (wildtype) and A220 were amplified and sequenced. Two mutant PfCRT haplotypes on residues 72-76 (CVIET and CVINT) were identified with a prevalence of 18.6% and 2.3%, respectively. Interestingly, the CVINT haplotype was identified for the first time in this region. A220S changes were found in 16.3% of samples occurring concurrently with the CVIET haplotype, while a Q271E mutation occurred in a wildtype isolate. The reduced prevalence of the PfCRT mutant alleles in this study may suggest a gradual disappearance of chloroquine-resistant malaria parasites following reduced drug pressure. It may also be an indicator of the ability of malaria parasites to develop resistance gradually against the current first-line regimen.

Currently, drug repurposing is an alternative to novel drug development for the treatment of COVID-19 patients. The antimalarial drug chloroquine (CQ) and its metabolite hydroxychloroquine (HCQ) are currently being tested in several clinical studies as potential candidates to limit SARS-CoV-2-mediated morbidity and mortality. CQ and HCQ (CQ/HCQ) inhibit pH-dependent steps of SARS-CoV-2 replication by increasing pH in intracellular vesicles and interfere with virus particle delivery into host cells. Besides direct antiviral effects, CQ/HCQ specifically target extracellular zinc to intracellular lysosomes where it interferes with RNA-dependent RNA polymerase activity and coronavirus replication. As zinc deficiency frequently occurs in elderly patients and in those with cardiovascular disease, chronic pulmonary disease, or diabetes, we hypothesize that CQ/HCQ plus zinc supplementation may be more effective in reducing COVID-19 morbidity and mortality than CQ or HCQ in monotherapy. Therefore, CQ/HCQ in combination with zinc should be considered as additional study arm for COVID-19 clinical trials.

Chloroquine was among the first of several effective drug treatments against malaria until the onset of chloroquine resistance. In light of diminished clinical efficacy of chloroquine as an antimalarial therapeutic, there is potential in efforts to adapt chloroquine for other clinical applications, such as in combination therapies and in diagnostics. In this context, we designed and synthesized a novel asymmetrical squaraine dye coupled with chloroquine (SQR1-CQ). In this study, SQR1-CQ was used to label live Plasmodium falciparum (P. falciparum) parasite cultures of varying sensitivities towards chloroquine. SQR1-CQ positively stained ring, mature trophozoite and schizont stages of both chloroquine–sensitive and chloroquine–resistant P. falciparum strains. In addition, SQR1-CQ exhibited significantly higher fluorescence, when compared to a chloroquine-BODIPY (borondipyrromethene) conjugate. We also achieved successful SQR1-CQ labelling of P. falciparum directly on thin blood smear preparations. Drug efficacy experiments measuring half-maximal inhibitory concentration (IC50) showed lower concentration of effective inhibition against resistant strain K1 by SQR1-CQ compared to conventional chloroquine. Taken together, the versatile and highly fluorescent labelling capability of SQR1-CQ and promising preliminary IC50 findings potentiates it to be further developed as a promising diagnostic bioimaging tool with drug efficacy against chloroquine-resistant P. falciparum.

Background: The antimalarial drug chloroquine and antimicrobial drug azithromycin have received significant attention during the current COVID-19 pandemic. Both drugs can alter cardiac electrophysiology and have been associated with drug-induced arrhythmias. Meanwhile, sympathetic activation is commonly observed during systemic inflammation and oxidative stress (e.g., in SARS-CoV-2 infection), and may influence the electrophysiological effects of chloroquine and azithromycin. Here, we investigated the effect of beta-adrenergic stimulation on proarrhythmic properties of chloroquine and azithromycin using a detailed in silico model of ventricular electrophysiology. Methods: Concentration-dependent chloroquine and azithromycin-induced alterations in ion-channel function were incorporated into the Heijman canine ventricular cardiomyocyte model. Single and combined drug effects on action-potential (AP) properties were analyzed using a population of 592 models accommodating inter-individual variability. Sympathetic stimulation was simulated by an increase in pacing rate and experimentally validated isoproterenol-induced changes in ion-channel function. Results: At 1 Hz pacing, therapeutic doses of chloroquine and azithromycin (5 and 20 µM, respectively) individually prolonged AP duration (APD) by 33% and 13%. Their combination produced synergistic APD prolongation (+161%) with incidence of proarrhythmic early afterdepolarizations in 53.5% of models. Increasing the pacing frequency to 2 Hz shortened APD and together with 1 µM isoproterenol corrected the drug-induced APD prolongation. No afterdepolarizations occurred following increased rate and simulated application of 0.1-1 µM isoproterenol. Conclusion: Sympathetic stimulation limits chloroquine- and azithromycin-induced proarrhythmia by reducing their APD-prolonging effect, suggesting the importance of heart rate and autonomic status monitoring in particular conditions (e.g., COVID-19).

Chloroquine (CQ) and its derivate hydroxychloroquine (HCQ), the compounds with recognized ability to suppress autophagy, have been tested in experimental works and in clinical trials as adjuvant therapy for the treatment of cancers of different origin to increase the efficacy of cytotoxic agents. Such strategy can be effective to overcome the resistance to standard chemotherapy or anti-angiogenic therapy. This review presents the results of combined application of CQ/HCQ with conventional chemotherapy drugs (doxorubicin, paclitaxel, platinum-based compounds, gemcitabine, tyrosine kinases and PI3K/Akt/mTOR inhibitors, and other agents) for the treatment of different malignancies obtained in experiments on cultured cancer cells and on animal xenograft models, with a few examples of clinical trials. The effects of such approach on viability of cancer cells and tumor growth, as well as autophagy-dependent and independent molecular mechanisms underlying cellular responses of cancer cells to CQ/HCQ are summarized. Although the majority of experimental studies in vitro and in vivo have shown that CQ/HCQ can effectively sensitize the cancer cells to cytotoxic agents and increase the potential of chemotherapy, the results of clinical trials are often inconsistent. Although pharmacological suppression of autophagy remains a promising tool for increasing the efficacy of standard chemotherapy, the development of more specific compounds is required.

Novel Coronavirus (2019-nCOV) causes inflammatory response with worsening symptoms. Classification of potential anti-viral and anti-inflammatory drugs in managing the symptoms of the COVID-19 and reducing morbidity is important. The objective of this study is to identify a group of drugs, best suited for COVID-19 treatment based on recent developments in clinical trials, FDA drug evaluation, directions and developments and from drug therapies globally. Online literature search was done on Medline, PubMed and google scholar databases for studies on various treatments and drug therapies for COVID-19 and relevant studies were identified and the identified drugs are described in detail as per their Pharmacological, pharmaceutical properties of the drugs, mechanism of action, current COVID-19 drug therapy, contraindications and drug-drug interactions Certain drugs can inhibit action against viral infection and protect lungs from severe inflammatory response. This article summarizes several drugs like Hydroxychloroquine, Chloroquine, Remdesivir, Favipiravir, Lopinavir, Ritonavir, Dexamethasone, Ivermectin, Baricitinib, Casirivimab / imdevimab, Bamlanivimab along with auxiliary treatment like convalescent plasma transfusion. Remdesivir is first drug approved by FDA. Hydroxychloroquine, dexamethasone and remdesivir are showing results against COVID-19 but it is important to test the efficacy and safety of such drugs though some drugs have shown remarkable results.

Although phylogenetic analysis shows coronaviruses (CoV) share similar genome sequences, CoVs encode different number of proteins (5 to 14). The newly isolated viruses harbour more proteins than the old ones. Therefore, identifying the functional protein unites will benefits to understand the molecular interactions of the virus, and then identify molecular targets for antiviral drug. Here, the comparative in-silico analysis of 33 coronavirus proteomes show that coronaviruses harbour diverse number of protein functional motifs. Coronaviruses harbour wide-range of motifs including those involved in integrin-binding and ESCRT pathway before virus budding. For example, SARS-CoV-2, but not SARS-CoV-1, encodes PPxY motif, which is required for virus entry and budding of HIV, influenza and adenoviruses. The quinolone inulding the antiviral FGI-104 is able to block ESCRT pathway and viral budding and has been used against HIV, HCV and Ebola virus.

The emergence of chemoresistance in neoplastic cells is one of the major obstacles in cancer therapy. Autophagy was recently reported as one of the mechanisms that promote chemoresistance in cancer cells by protecting from apoptosis and driving senescence. Thus, understanding the role of autophagy and its underlying signaling pathways is crucial for the development of new therapeutic strategies to overcome chemoresistance. We have previously reported that PKCη is a stress-induced kinase that confers resistance in breast cancer cells against chemotherapy by inducing senescence. Here we show that PKCη promotes autophagy induced by ER and oxidative stress and facilitates the transition from autophagy to senescence. We demonstrate that PKCη knockdown reduces both the autophagic flux and markers of senescence. Additionally, using autophagy inhibitors, such as chloroquine and 3-methyladenine, we show that PKCη and autophagy are required for establishing senescence in MCF-7 in response to oxidative stress. Different drugs used in the clinic are known to induce autophagy and senescence in breast cancer cells. Our study proposes PKCη as a target for therapeutic intervention, acting in synergy with autophagy-inducing drugs, to overcome resistance and enhance cell death in breast cancer.

There is a long trail of research studies testing the in vitro and in vivo efficacy of chloroquine and its derivatives in treating and preventing infection by various coronavirus species. More recent findings have highlighted the possibility of treating patients infected with the 2019 novel coronavirus, SARS-CoV-2. This review describes the mechanism of coronavirus infection, the mechanism of action of chloroquine, and summarizes the available literature highlighting the efficacy of chloroquine as an anti-coronavirus agent. These findings should encourage the wider scientific community to conduct thorough research on the possible efficacy of chloroquine and its derivatives in treating and preventing SARS-CoV-2 infection.

We report the results of our study of approved drugs as potential treatments for COVID 19, based on the application of various bioinformatics predictive methods. The drugs studied include chloroquine, ivermectin, remdesivir, sofosbuvir, boceprevir, and α-difluoromethylornithine (DMFO). Our results indicate that these small molecules selectively bind to stable, kinetically active residues and residues adjoining them on the surface of proteins and inside protein pockets, and that some prefer hydrophobic over other active sites. Our approach is not restricted to viruses and can facilitate rational drug design, as well as improve our understanding of molecular interactions, in general.

COVID-19 (2019-nCoV) is a pandemic disease with an estimated mortality rate of 3.4% (estimated by the WHO as of March 3, 2020). Until now there is no antiviral drug and vaccine for COVID-19. The current overwhelming situation by COVID-19 patients in hospitals is likely to increase in the next few months. About 15 percent of patients with serious disease in COVID-19 require immediate health services. Rather than waiting for new anti-viral drugs or vaccines that take a few months to years to develop and test, several researchers and public health agencies are attempting to repurpose medicines that are already approved for another similar disease and have proved to be fairly effective. This study aims to identify FDA approved drugs that can be used for drug repurposing and identify biomarkers among high- risk and asymptomatic groups. In this study gene-disease association related to COVID-19 reported mild, severe symptoms and clinical outcomes were determined. The high-risk group was studied related to SARS-CoV-2 viral entry and life cycle by using Disgenet and compared with curated COVID-19 gene data sets from the CTD database. The overlapped gene sets were enriched and the selected genes were constructed for protein-protein interaction networks. Through interactome, key genes were identified for COVID-19 and also for high risk and asymptomatic groups. The key hub genes involved in COVID-19 were VEGFA, TNF, IL-6, CXCL8, IL10, CCL2, IL1B, TLR4, ICAM1, MMP9. The identified key genes were used for drug-gene interaction for drug repurposing. The chloroquine, lenalidomide, pentoxifylline, thalidome, sorafenib, pacitaxel, rapamycin, cortisol, statins were proposed to be probable drug repurposing candidates for the treatment of COVID-19. However, these predicted drug candidates need to be validated through randomized clinical trials. Also, a key gene involved in high risk and the asymptomatic group were identified, which can be used as probable biomarkers for early identification.

At a time when the world faces an emotional breakdown, crushing our dreams if not taking our lives, we realize that together we must fight the war against the COVID-19 outbreak even if almost the majority of the scientific community finds itself confined to home. Every day, like everyone else, we, scientists, listen to the latest news with its promises and announcements. Across the world, a surge of clinical trials trying to cure or slow down the coronavirus pandemic has been launched to bring hope instead of fear and despair. One first proposed clinical trial has drawn worldwide hype to the benefit of chloroquine (CQ), a well-known and broadly used anti-malarial drug, in the treatment of patients infected by the recently emerged deadly coronavirus (SARS-CoV-2). We should consider this information in the light of the long-standing anti-inflammatory and anti-viral properties of CQ-related drugs. Yet, none of the articles promoting the use of CQ in the current pandemic evoked a possible molecular or cellular mechanism of action that could account for any efficacy. Here, given the interaction of viruses with macroautophagy (hereafter referred to as autophagy), a CQ-sensitive anti-viral safeguard pathway, we would like to discuss the pros, but also the cons concerning the current therapeutic options targeting this process.

The novel coronavirus COVID- 19 disease is extremely contagious and has been spread worldwide. First COVID-19 case was identified in December, 2019 and within three months, more than one million affected cases and over 65,000 deaths have been reported. SARS-coronavirus 2 (SARS-CoV-2) also known as 2019-nCoV is a causative agent of COVID-19 disease and belongs to the SARS CoV (Severe Acute Respiratory Syndrome corona virus) family. The SARS-CoV-2 enters the human body by binding its viral surface spike protein with the host angiotensin-converting enzyme 2 (ACE2) receptors and cause infection. To prevent the virus entry and its transmission in the human body, we focused on the two domains of ACE2: i) the N-terminal extracellular binding domain (18-740 residues) reported for coronavirus spike interaction, and ii) the C-terminal cytoplasmic region (762-805 residues) to prevent the virus transmission. Therefore, we proposed: i) inhibition of receptor binding domain (RBD) of SARS-CoV-2 and human ACE2 protein may prevent the virus entry to the host and ii) inhibition of phosphorylation at Ser-787 of ACE2 protein may prevent the transmission of the virus in the COVID-19 patients. In the past, the critical role of Ser 787 in human ACE2 protein has been experimentally verified in SARS-CoV transmission, that upon binding to the receptor, SARS- CoV induces CKII- mediated phosphorylation of ACE2 at Ser-787 that in-turn facilitate virus entry to host cells, followed by replication and activation of ACE2, initiates downstream signaling leading to lung fibrosis. Therefore, in this study, we have suggested post-translational modification (PTM) O-β-GlcNAcylation, and two compounds Chloroquine and 2-hydroxybenzohydrazine might share the common pathways to prevent the COVID-19 infection in human. The addition of O-β-GlcNAcylation at same or neighboring Ser/ Thr residues results in phosphorylation inhibition and a change in protein structural and functional confirmations. Thereby, using neural networking methods, we have identified Ser/ Thr residues in ACE2 that are potential sites for phosphorylation and / or O-β-GlcNAcylation. Molecular docking showed that UDP-GlcNAc has more binding affinity with Ser-787 than the phosphoryl group. Moreover, chloroquine and 2-hydroxybenzohydrazine also showed great potential to bind at Ser-787 that may result in inhibition of Ser-787 phosphorylation and downstream signaling. Furthermore, O-β-GlcNAcylation, chloroquine and 2-hydroxybenzohydrazine showed their high affinity at ACE2-SARS-CoV-2receptor binding domain that may prevent the entry of SARS-CoV-2 into human body. In conclusion, inhibition of human ACE2 phosphorylation at Ser-787 and ACE2-SARS-CoV-2 binding domain could be promising targets against SARS-CoV-2 infection.