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Fulltext Correction: Lalani, S. and Poh, C.L. Flavonoids as Antiviral Agents for Enterovirus A71 (EV-A71). Viruses 2020, 12, 184

Lalani S, Poh CL

Viruses, 2020 Jun 30;12(7).
PMID: 32630136 DOI: 10.3390/v12070712

We have recently been made aware by Mr. Saravanan (National University of Singapore) thatthe structure of prunin flavonoid used in their study was different to the one that we reported [...].
Strategies to identify and develop antiviral peptides

Poh CL, Lalani S

Vitam Horm, 2021;117:17-46.
PMID: 34420580 DOI: 10.1016/bs.vh.2021.06.008

The emergence and re-emergence of viral pathogens capable of causing epidemics or pandemics pose a serious healthcare burden. Small molecule antivirals used in conventional therapy have given rise to the severe problem of viral resistance against them. Peptides are generally considered safe, effective and are less likely to induce viral resistance. Antiviral peptides can be identified from screening of phage display of combinational peptide libraries, peptide array libraries or designed against viral targets. Limitations of peptides such as bioavailability can be improved with chemical modifications. Nanotechnology can further improve the stability of peptides in systemic circulation and enhance the antiviral activity of peptides, making them an appealing therapeutic option.
Fulltext Flavonoids as Antiviral Agents for Enterovirus A71 (EV-A71)

Lalani S, Poh CL

Viruses, 2020 02 06;12(2).
PMID: 32041232 DOI: 10.3390/v12020184

Flavonoids are natural biomolecules that are known to be effective antivirals. These biomolecules can act at different stages of viral infection, particularly at the molecular level to inhibit viral growth. Enterovirus A71 (EV-A71), a non-enveloped RNA virus, is one of the causative agents of hand, foot and mouth disease (HFMD), which is prevalent in Asia. Despite much effort, no clinically approved antiviral treatment is available for children suffering from HFMD. Flavonoids from plants serve as a vast reservoir of therapeutically active constituents that have been explored as potential antiviral candidates against RNA and DNA viruses. Here, we reviewed flavonoids as evidence-based natural sources of antivirals against non-picornaviruses and picornaviruses. The detailed molecular mechanisms involved in the inhibition of EV-A71 infections are discussed.
Fulltext Antiviral peptides against Enterovirus A71 causing hand, foot and mouth disease

Lalani S, Gew LT, Poh CL

Peptides, 2021 Feb;136:170443.
PMID: 33171280 DOI: 10.1016/j.peptides.2020.170443

The emergence of new and resistant viruses is a serious global burden. Conventional antiviral therapy with small molecules has led to the development of resistant mutants. In the case of hand, foot and mouth disease (HFMD), the absence of a US-FDA approved vaccine calls for urgent need to develop an antiviral that could serve as a safe, potent and robust therapy against the neurovirulent Enterovirus A71 (EV-A71). Natural peptides such as lactoferrin, melittin and synthetic peptides such as SP40, RGDS and LVLQTM have been studied against EV-A71 and have shown promising results as potent antivirals in pre-clinical studies. Peptides are considered safe, efficacious and pose fewer chances of resistance. Poor pharmacokinetic features of peptides can be overcome by the use of chemical modifications to improve in vivo delivery particularly by oral route. The use of nanotechnology can remarkably assist in the oral delivery of peptides and enhance stability in vivo. This can greatly increase patient compliance and make it more attractive as antiviral therapy.
Apoptosis in Acanthamoeba castellanii belonging to the T4 genotype

Baig AM, Lalani S, Khan NA

J Basic Microbiol, 2017 Jul;57(7):574-579.
PMID: 28466971 DOI: 10.1002/jobm.201700025

Here we describe features of apoptosis in unicellular Acanthamoeba castellanii belonging to the T4 genotype. When exposed to apoptosis-inducing compounds such as doxorubicin, A. castellanii trophozoites exhibited cell shrinkage and membrane blebbing as observed microscopically, DNA fragmentation using agarose gel electrophoresis, and phosphatidylserine (PS) externalization using annexin V immunostaining. Overall, these findings suggest the existence of apoptosis in A. castellanii possibly mediated by intrinsic apoptotic cascade. Further research in this field could provide avenues to selectively induce apoptosis in A. castellanii by triggering intrinsic apoptotic cascade.
Fulltext Functional Insights into Silymarin as an Antiviral Agent against Enterovirus A71 (EV-A71)

Lalani S, Masomian M, Poh CL

Int J Mol Sci, 2021 Aug 15;22(16).
PMID: 34445463 DOI: 10.3390/ijms22168757

Enterovirus A71 (EV-A71) is a major neurovirulent agent capable of causing severe hand, foot and mouth disease (HFMD) associated with neurological complications and death. Currently, no FDA-approved antiviral is available for the treatment of EV-A71 infections. The flavonoid silymarin was shown to exert virucidal effects, but the binding site on the capsid was unknown. In this study, the ligand interacting site of silymarin was determined in silico and validated in vitro. Moreover, the potential of EV-A71 to develop resistance against silymarin was further evaluated. Molecular docking of silymarin with the capsid of EV-A71 indicated that silymarin binds to viral protein 1 (VP1) of EV-A71, specifically at the GH loop of VP1. The in vitro binding of silymarin with VP1 of EV-A71 was validated using recombinant VP1 through ELISA competitive binding assay. Continuous passaging of EV-A71 in the presence of silymarin resulted in the emergence of a mutant carrying a substitution of isoleucine by threonine (I97T) at position 97 of the BC loop of EV-A71. The mutation was speculated to overcome the inhibitory effects of silymarin. This study provides functional insights into the underlying mechanism of EV-A71 inhibition by silymarin, but warrants further in vivo evaluation before being developed as a potential therapeutic agent.
Fulltext Molecular Docking of SP40 Peptide towards Cellular Receptors for Enterovirus 71 (EV-A71)

Masomian M, Lalani S, Poh CL

Molecules, 2021 Oct 30;26(21).
PMID: 34770987 DOI: 10.3390/molecules26216576

Enterovirus 71 (EV-A71) is one of the predominant etiological agents of hand, foot and mouth disease (HMFD), which can cause severe central nervous system infections in young children. There is no clinically approved vaccine or antiviral agent against HFMD. The SP40 peptide, derived from the VP1 capsid of EV-A71, was reported to be a promising antiviral peptide that targeted the host receptor(s) involved in viral attachment or entry. So far, the mechanism of action of SP40 peptide is unknown. In this study, interactions between ten reported cell receptors of EV-A71 and the antiviral SP40 peptide were evaluated through molecular docking simulations, followed by in vitro receptor blocking with specific antibodies. The preferable binding region of each receptor to SP40 was predicted by global docking using HPEPDOCK and the cell receptor-SP40 peptide complexes were refined using FlexPepDock. Local molecular docking using GOLD (Genetic Optimization for Ligand Docking) showed that the SP40 peptide had the highest binding score to nucleolin followed by annexin A2, SCARB2 and human tryptophanyl-tRNA synthetase. The average GoldScore for 5 top-scoring models of human cyclophilin, fibronectin, human galectin, DC-SIGN and vimentin were almost similar. Analysis of the nucleolin-SP40 peptide complex showed that SP40 peptide binds to the RNA binding domains (RBDs) of nucleolin. Furthermore, receptor blocking by specific monoclonal antibody was performed for seven cell receptors of EV-A71 and the results showed that the blocking of nucleolin by anti-nucleolin alone conferred a 93% reduction in viral infectivity. Maximum viral inhibition (99.5%) occurred when SCARB2 was concurrently blocked with anti-SCARB2 and the SP40 peptide. This is the first report to reveal the mechanism of action of SP40 peptide in silico through molecular docking analysis. This study provides information on the possible binding site of SP40 peptide to EV-A71 cellular receptors. Such information could be useful to further validate the interaction of the SP40 peptide with nucleolin by site-directed mutagenesis of the nucleolin binding site.
Isolation of Balamuthia mandrillaris-specific antibody fragments from a bacteriophage antibody display library

Siddiqui R, Kulsoom H, Lalani S, Khan NA

Exp Parasitol, 2016 Jul;166:94-6.
PMID: 27055361 DOI: 10.1016/j.exppara.2016.04.001

Balamuthia mandrillaris is a protist pathogen that can cause encephalitis with a mortality rate of more than 95%. Early diagnosis followed by aggressive treatment is a pre-requisite for successful prognosis. Current methods for identifying this organism rely on culture and microscopy, antibody-based methods using animals, or involve the use of molecular tools that are expensive. Here, we describe the isolation of antibody fragments that can be used for the unequivocal identification of B. mandrillaris. B. mandrillaris-specific antibody fragments were isolated from a bacteriophage antibody display library. Individual clones were studied by enzyme-linked immunosorbent assay, and immunofluorescence. Four antibody clones showed specific binding to B. mandrillaris. The usefulness of phage antibody display technology as a diagnostic tool for isolating antibody fragments against B. mandrillaris antigens and studying their biological role(s) is discussed further.
Molecular mechanism of L-SP40 peptide and in vivo efficacy against EV-A71 in neonatal mice

Lalani S, Tan SH, Tan KO, Lim HX, Ong KC, Wong KT, et al.

Life Sci, 2021 Dec 15;287:120097.
PMID: 34715144 DOI: 10.1016/j.lfs.2021.120097

AIMS: Enterovirus A71 (EV-A71) is an etiological agent of hand foot and mouth disease (HFMD) and has the potential to cause severe neurological infections in children. L-SP40 peptide was previously known to inhibit EV-A71 by prophylactic action. This study aimed to identify the mechanism of inhibition in Rhabdomyosarcoma (RD) cells and in vivo therapeutic potential of L-SP40 peptide in a murine model.
MAIN METHODS: A pull-down assay was performed to identify the binding partner of the L-SP40 peptide. Co-immunoprecipitation and co-localization assays with the L-SP40 peptide were employed to confirm the receptor partner in RD cells. The outcomes were validated using receptor knockdown and antibody blocking assays. The L-SP40 peptide was further evaluated for the protection of neonatal mice against lethal challenge by mouse-adapted EV-A71.
KEY FINDINGS: The L-SP40 peptide was found to interact and co-localize with nucleolin, the key attachment receptor of Enteroviruses A species, as demonstrated in the pull-down, co-immunoprecipitation and co-localization assays. Knockdown of nucleolin from RD cells led to a significant reduction of 3.5 logs of viral titer of EV-A71. The L-SP40 peptide demonstrated 80% protection of neonatal mice against lethal challenge by the mouse-adapted virus with a drastic reduction in the viral loads in the blood (~4.5 logs), skeletal muscles (1.5 logs) and brain stem (1.5 logs).
SIGNIFICANCE: L-SP40 peptide prevented severe hind limb paralysis and death in suckling mice and could serve as a potential broad-spectrum antiviral candidate to be further evaluated for safety and potency in future clinical trials against EV-A71.
Synthesis of novel inhibitors of α-glucosidase based on the benzothiazole skeleton containing benzohydrazide moiety and their molecular docking studies

Taha M, Ismail NH, Lalani S, Fatmi MQ, Atia-Tul-Wahab, Siddiqui S, et al.

Eur J Med Chem, 2015 Mar 6;92:387-400.
PMID: 25585009 DOI: 10.1016/j.ejmech.2015.01.009

In an effort to design and synthesize a new class of α-glucosidase inhibitor, we synthesized benzothiazole hybrid having benzohydrazide moiety (5). Compound 5 was reacted with various substituted aryl aldehyde to generate a small library of compounds 6-35. Synthesis of compounds was confirmed by the spectral information. These compounds were screened for their α-glucosidase activity. They showed a varying degree of α-glucosidase inhibition with IC50 values ranging between 5.31 and 53.34 μM. Compounds 6, 7, 9-16, 19, 21-30, 32-35 showed superior activity as compared to standard acarbose (IC50 = 906 ± 6.3 μM). This has identified a new class of α-glucosidase inhibitors. The predicted physico-chemical properties indicated the drug appropriateness for most of these compounds, as they obey Lipinski's rule of five (RO5). A hybrid B3LYP density functional theory (DFT) was employed for energy, minimization of 3D structures for all synthetic compounds using 6-311 + G(d,p) basis sets followed by molecular docking to explore their interactions with human intestinal C- and N-terminal domains of α-glucosidase. All compounds bind to the prospective allosteric site of the C- terminal domain, and consequently, may be considered as mixed inhibitors. It was hypothesized that both the dipole moment and H-bond interactions govern the biological activation of these compounds.
'Targeting the feast of a sleeping beast': Nutrient and mineral dependencies of encysted Acanthamoeba castellanii

Baig AM, Khan NA, Katyara P, Lalani S, Baig R, Nadeem M, et al.

Chem Biol Drug Des, 2021 01;97(1):18-27.
PMID: 32602961 DOI: 10.1111/cbdd.13755

Acanthamoeba spp. cause a corneal infection, Acanthamoeba keratitis (AK), and a cerebral infection, granulomatous amoebic encephalitis (GAE). Though aggressive chemotherapy has been able to kill the active trophozoite form of Acanthamoeba, the encysted form of this parasite has remained problematic to resist physiological concentrations of drugs. The emergence of encysted amoeba into active trophozoite form poses a challenge to eradicate this parasite. Acanthamoeba trophozoites have active metabolic machinery that furnishes energy in the form of ATPs by subjecting carbohydrates and lipids to undergo pathways including glycolysis and beta-oxidation of free fatty acids, respectively. However, very little is known about the metabolic preferences and dependencies of an encysted trophozoite on minerals or potential nutrients that it consumes to live in an encysted state. Here, we investigate the metabolic and nutrient preferences of the encysted trophozoite of Acanthamoeba castellanii and the possibility to target them by drugs that act on calcium ion dependencies of the encysted amoeba. The experimental assays, immunostaining coupled with bioinformatics tools show that the encysted Acanthamoeba uses diverse nutrient pathways to obtain energy in the quiescent encysted state. These findings highlight potential pathways that can be targeted in eradicating amoebae cysts successfully.
Synthesis and molecular docking studies of potent α-glucosidase inhibitors based on biscoumarin skeleton

Khan KM, Rahim F, Wadood A, Kosar N, Taha M, Lalani S, et al.

Eur J Med Chem, 2014 Jun 23;81:245-52.
PMID: 24844449 DOI: 10.1016/j.ejmech.2014.05.010

In our effort directed toward the discovery of new anti-diabetic agent for the treatment of diabetes, a library of biscoumarin derivative 1-18 was synthesized and evaluated for α-glucosidase inhibitory potential. All eighteen (18) compounds displayed assorted α-glucosidase activity with IC50 values 16.5-385.9 μM, if compared with the standard acarbose (IC50 = 906 ± 6.387 μM). In addition, molecular docking studies were carried out to explore the binding interactions of biscoumarin derivatives with the enzyme. This study has identified a new class of potent α-glucosidase inhibitors.