Targeting of essential mycobacterial replication enzyme DnaG primase revealed Mitoxantrone and Vapreotide as novel mycobacterial growth inhibitors.

Tuberculosis (TB) is the second leading cause of mortality after COVID-19, with a global death toll of 1.6 million in 2021. The escalating situation of drug-resistant forms of TB has threatened the current TB management strategies. New therapeutics with novel mechanisms of action are urgently required to address the current global TB crisis. The essential mycobacterial primase DnaG with no structural homology to homo sapiens presents itself as a good candidate for drug targeting. In the present study, Mitoxantrone and Vapreotide, two FDA-approved drugs, were identified as potential anti-mycobacterial agents. Both Mitoxantrone and Vapreotide exhibit a strong Minimum Inhibitory Concentration (MIC) of ≤25µg/ml against both the virulent (M.tb-H37Rv) and avirulent (M.tb-H37Ra) strains of M.tb. Extending the validations further revealed the inhibitory potential drugs in ex vivo conditions. Leveraging the computational high-throughput multi-level docking procedures from the pool of ~2700 FDA-approved compounds, Mitoxantrone and Vapreotide were screened out as potential inhibitors of DnaG. Extensive 200 ns long all-atoms molecular dynamic simulation of DnaGDrugs complexes revealed that both drugs bind strongly and stabilize the DnaG during simulations. Reduced solvent exposure and confined motions of the active centre of DnaG upon complexation with drugs indicated that both drugs led to the closure of the active site of DnaG. From this study's findings, we propose Mitoxantrone and Vapreotide as potential anti-mycobacterial agents, with their novel mechanism of action against mycobacterial DnaG.

Atosiban and Rutin exhibit anti-mycobacterial activity - An integrated computational and biophysical insight toward drug repurposing strategy against Mycobacterium tuberculosis targeting its essential enzyme HemD.

With the advancements of high throughput computational screening procedures, drug repurposing became the privileged framework for drug discovery. The structure-based drug discovery is the widely used method of drug repurposing, consisting of computational screening of compounds and testing them in-vitro. This current method of repurposing leaves room for mechanistic insights into how these screened hits interact with and influence their targets. We addressed this gap in the current study by integrating highly sensitive biophysical methods into existing computational repurposing methods. We also corroborated our computational and biophysical findings on H37Rv for the anti-mycobacterial action of selected drugs in-vitro and ex-vivo conditions. Atosiban and Rutin were screened as highly interacting hits against HemD through multi-stage docking and were cross-validated in biophysical studies. The affinity of these drugs (K ~ 106 M-1) was quantified using fluorescence quenching studies. Differential Scanning Fluorimetry (DSF) and urea-based chemical denaturation studies revealed a destabilizing effect of these drugs on target which was further validated using MD simulations. Conformational rearrangements of secondary structures were established using CD spectra and intrinsic fluorescence. Furthermore, Atosiban and Rutin inhibited M.tb growth in-vitro and ex-vivo while remaining non-toxic to mice peritoneal macrophages.

SARS CoV-2 spike protein variants exploit DC-SIGN/DC-SIGNR receptor for evolution and severity: an in-silico insight.

The Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is related with the COVID-19 pandemic. Recent spike protein variations have had an effect on the transmission of the virus. In addition to ACE-2, spike proteins can employ DC-SIGN and its analogous receptor, DC-SIGNR, for host evasion. Spike variations in the DC-SIGN interaction region and role of DC-SIGN in immune evasion have not been well defined. To understand the spike protein variations and their binding mode, phylogenetic analysis of the complete GISAID (Global Initiative for Sharing Avian Influenza Data) data of the SARS-CoV-2 spike protein was considered. In addition, an in silico knockout network evaluation of the SARS-CoV-2 single-cell transcriptome was conducted to determine the key role of DC-SIGN/R in immunological dysregulation. Within the DC-SIGN-interacting region of the SARS-CoV spike protein, the spike protein of SARS-CoV-2 displayed remarkable similarity to the SARS-CoV spike protein. Surprisingly, the phylogenetic analysis revealed that the SARS-CoV-2's spike exhibited significantly diverse variants in the DC-SIGN interaction domain, which altered the frequency of these variants. The variation within the DC-SIGN-interacting domain of spike proteins affected the binding of a limited number of variants with DC-SIGN and DC-SIGNR and affected their evolution. MMGBSA binding free energies evaluation differed for variants from those of the wild type, suggesting the influence of substitution mutations on the interaction pattern. In silico knockout network analysis of the single-cell transcriptome of Bronchoalveolar Lavage and peripheral blood mononuclear cells revealed that SARS-CoV-2 altered DC-SIGN/R signaling. Early surveillance of diverse SARS-CoV-2 strains could preclude a worsening of the pandemic and facilitate the development of an optimum vaccine against variations. The spike Receptor Binding Domain genetic variants are thought to boost SARS CoV-2 immune evasion, resulting in its higher longevity. Supplementary Information: The online version contains supplementary material available at 10.1007/s13337-023-00820-3.

Mechanistic and structural insight into R2R3-MYB transcription factor in plants: molecular dynamics based binding free energy analysis.

The MYB transcription factor (TF) family is essential for various plant growth and development processes, including responses to biotic and abiotic stresses. This study investigated the R2R3-MYB protein structure from five plants, including cereal crops. The R2R3-MYB protein structure was docked with the DNA structure, and the best complexes were selected for two runs of molecular dynamics (MD) simulations to investigate the key interacting residues and conformational changes in the R2R3-MYB proteins caused by DNA binding. The MM/PBSA method calculated the binding free energy for each R2R3-MYB protein-DNA complex, showing strong interaction. Hydrophobic and hydrogen bonds significantly stabilized the R2R3-MYB protein-DNA complexes. The principal component analysis showed high restrictions on the movement of protein atoms in the phase space. A similar MD simulation analysis was performed using the crystal structure of the R2R3-MYB protein-DNA complex from Arabidopsis thaliana, and the generated complexes resembled the X-ray crystal structure. This is the first detailed study on the R2R3-MYB protein-DNA complex in cereal crops, providing a cost-effective solution to identify the key interacting residues and analyze the conformational changes in the MYB domain before and after DNA binding.Communicated by Ramaswamy H. Sarma.

Correction: Self-reported Morisky Eight-item Medication Adherence Scale for Statins Concords with the Pill Count Method and Correlates with Serum Lipid Profile Parameters and Serum HMGCoA Reductase Levels.

[This corrects the article DOI: 10.7759/cureus.6542.].

Potential Repurposed Drug Candidates for Tuberculosis Treatment: Progress and Update of Drugs Identified in Over a Decade.

The devastating impact of Tuberculosis (TB) has been a menace to mankind for decades. The World Health Organization (WHO) End TB Strategy aims to reduce TB mortality up to 95% and 90% of overall TB cases worldwide, by 2035. This incessant urge will be achieved with a breakthrough in either a new TB vaccine or novel drugs with higher efficacy. However, the development of novel drugs is a laborious process involving a timeline of almost 20-30 years with huge expenditure; on the other hand, repurposing previously approved drugs is a viable technique for overcoming current bottlenecks in the identification of new anti-TB agents. The present comprehensive review discusses the progress of almost all the repurposed drugs that have been identified to the present day (∼100) and are in the development or clinical testing phase against TB. We have also emphasized the efficacy of repurposed drugs in combination with already available frontline anti-TB medications along with the scope of future investigations. This study would provide the researchers a detailed overview of nearly all identified anti-TB repurposed drugs and may assist them in selecting the lead compounds for further in vivo/clinical research.

A Case of Fabry Disease With Lacrimal Gland Involvement.

Fabry disease is an X-linked lysosomal storage disease resulting from an error in the glycosphingolipid metabolic pathway, which leads to accumulation of globotriaosylceramide in lysosomes of the skin, kidneys, heart, brain, and other organs. There are no existing reports of histologically proven lacrimal gland involvement in Fabry disease. The authors report the case of a 26-year-old male with Fabry disease who presented with bilateral upper eyelid dermatochalasis, steatoblepharon, and prolapsed lacrimal glands. The patient underwent surgical repair of the upper eyelids and biopsy of the lacrimal glands. The pathologic assessment demonstrated lamellated intracytoplasmic inclusions characteristic of Fabry disease. The prevalence of globotriaosylceramide lacrimal gland deposition in Fabry disease and the effect on lacrimal gland morphology and function have yet to be determined.

Immuno-informatics guided designing of a multi-epitope vaccine against Dengue and Zika.

Dengue and zika are amongst the most prevalent mosquito-borne diseases caused by closely related members Dengue virus (DENV) and Zika virus (ZIKV), respectively, of the Flaviviridae family. DENV and ZIKV have been reported to co-infect several people, resulting in fatalities across the world. A vaccine that can safeguard against both these pathogens concurrently, can offer several advantages. This study has employed immuno-informatics for devising a multi-epitope, multi-pathogenic vaccine against both these viruses. Since, the two viruses share a common vector source, whose salivary components are reported to aid viral pathogenesis; antigenic salivary proteins from Aedes aegypti were also incorporated into the design of the vaccine along with conserved structural and non-structural viral proteins. Conserved B- and T-cell epitopes were identified for all the selected antigenic proteins. These epitopes were merged and further supplemented with ß-defensin as an adjuvant, to yield an immunogenic vaccine construct. In-silico 3D modeling and structural validation of the vaccine construct was conducted, followed by its molecular docking and molecular dynamics simulation studies with human TLR2. Immune simulation study was also performed, and it further provided support that the designed vaccine can mount an effective immune response and hence provide protection against both DENV and ZIKV. Communicated by Ramaswamy H. Sarma.

Early Cutaneous Manifestations of COVID-19: A Systematic Review and Public Health Implications.

INTRODUCTION: Cutaneous manifestations before other symptoms have great potential for early COVID-19 diagnosis to prevent surge. METHODS: We conducted a search of PubMed and Embase databases through April 11, 2021 to include 39 studies reporting skin manifestations occurring prior to any other COVID-19 symptoms in laboratory-confirmed cases. RESULTS: Ninety-seven patients were included. Urticarial (24.7%) and maculopapular (22.7%) lesions were most common, followed by pernio (17.5%), vesicular (14.4%), papulosquamous (8.2%), and purpuric (5.1%) lesions. Cutaneous to systemic symptom latency ranged from 2 to 20 days in cases that reported it (26%), while skin lesions were the only presentation in 23 cases (23.7%). Skin lesions were the only COVID-19 manifestation in 58.8% of pernio, 40% of vesicular, 16.6% of urticarial, 18.2% of maculopapular, and 12.5% of papulosquamous presymptomatic cases. Although sample size is limited, all purpuric cases developed other symptom(s) later. CONCLUSIONS: Pernio and purpuric lesions have been well-associated with COVID-19, but papulosquamous, vesicular, mild maculopapular, and urticarial lesions can easily be dismissed as unrelated to COVID-19. Pernio lesions are thought to be related to strong immune response and low contagiousness, while purpuric and vesicular cases are speculated to be related to higher SARS-CoV2 viral load, severity, and contagiousness. All rashes, even without other symptoms, should necessitate high level of suspicion for isolation or contact tracing.

A Review of Morphologic Findings in Peripheral Blood Smears of COVID-19 Patients.

INTRODUCTION: Peripheral smear examination is a simple and cost-effective test that is routinely performed while monitoring patients diagnosed with COVID-19. We sought to summarize the peripheral blood morphologic findings in patients with COVID-19 infection. METHODS: A systematic review was conducted using a standardized keyword search on Medline database (PubMed), med RXIV, Google Scholar, EMBASE, and SCOPUS for studies discussing peripheral blood smear or morphologic blood findings in patients diagnosed with COVID-19. RESULTS: A total of 28 studies were included in the review. Normocytic normochromic anemia was the most frequently encountered red blood cell finding. Neutrophilia was seen in most of the studies. A variety of morphological changes were observed in neutrophils, including pyknotic nuclei, variable shapes, toxic granules, and cytoplasmic vacuolization. Hyposegmented neutrophils, pseudo-Pegler Huet forms, and hypogranular forms were common findings reported by many studies. Lymphopenia was reported by most studies. Lymphocytes showed numerous morphological changes, including reactive forms, Downey forms, increased large granular lymphocytes, and plasmacytoid cells. The presence of giant platelets was seen frequently. CONCLUSIONS: The peripheral blood in COVID-19 shows a spectrum of findings, mostly reactive changes in neutrophils, monocytes, lymphocytes, and platelets. Increased neutrophil/lymphocyte ratio and higher neutrophil counts have been associated with poor prognosis, which potentially could help triage patients, but this needs to be confirmed in larger studies.

Amyloid fibrillation of the glaucoma associated myocilin protein is inhibited by epicatechin gallate (ECG).

Inherited glaucoma is a recent addition to the inventory of diseases arising due to protein misfolding. Mutations in the olfactomedin (OLF) domain of myocilin are the most common genetic cause behind this disease. Disease associated variants of m-OLF are predisposed to misfold and aggregate in the trabecular meshwork (TM) tissue of the eye. In recent years, the nature of these aggregates was revealed to exhibit the hallmarks of amyloids. Amyloid aggregates are highly stable structures that are formed, often with toxic consequences in a number of debilitating diseases. In spite of its clinical relevance the amyloidogenic nature of m-OLF has not been studied adequately. Here we have studied the amyloid fibrillation of m-OLF and report ECG as an inhibitor against it. Using biophysical and biochemical assays, coupled with advanced microscopic evaluations we show that ECG binds and stabilizes native m-OLF and thus prevents its aggregation into amyloid fibrils. Furthermore, we have used REMD simulations to delineate the stabilizing effects of ECG on the structure of m-OLF. Collectively, we report ECG as a molecular scaffold for designing and testing of novel inhibitors against m-OLF amyloid fibrillation.

Molecular insights into the critical role of gallate moiety of green tea catechins in modulating prion fibrillation, cellular internalization, and neuronal toxicity.

Transmissible spongiform encephalopathies (TSEs) or prion diseases are fatal neurodegenerative diseases with no approved therapeutics. TSE pathology is characterized by abnormal accumulation of amyloidogenic and infectious prion protein conformers (PrPSc) in the central nervous system. Herein, we examined the role of gallate group in green tea catechins in modulating the aggregation of human prion protein (HuPrP) using two green tea constituents i.e., epicatechin 3-gallate (EC3G; with intact gallate ring) and epigallocatechin (EGC; without gallate ring). Molecular docking indicated distinct differences in hydrogen bonding and hydrophobic interactions of EC3G and EGC at the ß2-α2 loop of HuPrP. These differences were substantiated by 44-fold higher KD for EC3G as compared to EGC with the former significantly reducing Thioflavin T (ThT) binding aggregates of HuPrP. Conformational alterations in HuPrP aggregates were validated by particle sizing, AFM analysis and A11 and OC conformational antibodies. As compared to EGC, EC3G showed relatively higher reduction in toxicity and cellular internalization of HuPrP oligomers in Neuro-2a cells. Additionally, EC3G also displayed higher fibril disaggregating properties as observed by ThT kinetics and electron microscopy. Our observations were supported by molecular dynamics (MD) simulations that showed markedly reduced α2-α3 and ß2-α2 loop mobilities in presence of EC3G that may lead to constriction of HuPrP conformational space with lowered ß-sheet conversion. In totality, gallate moiety of catechins play key role in modulating HuPrP aggregation, and toxicity and could be a new structural motif for designing therapeutics against prion diseases and other neurodegenerative disorders.

Correction: Amyloid fibrillation of the glaucoma associated myocilin protein is inhibited by epicatechin gallate (ECG).

[This corrects the article DOI: 10.1039/D2RA05061G.].

Antitussive noscapine and antiviral drug conjugates as arsenal against COVID-19: a comprehensive chemoinformatics analysis.

Coronavirus pandemic has caused a vast number of deaths worldwide. Thus creating an urgent need to develop effective counteragents against novel coronavirus disease (COVID-19). Many antiviral drugs have been repurposed for treatment but implicated minimal recovery, which further advanced the need for clearer insights and innovation to derive effective therapeutics. Strategically, Noscapine, an approved antitussive drug with positive effects on lung linings may show favorable outcomes synergistically with antiviral drugs in trials. Hence, we have theoretically examined the combinatorial drug therapy by culminating the existing experimental results with in silico analyses. We employed the antitussive noscapine in conjugation with antiviral drugs (Chloroquine, Umifenovir, Hydroxychloroquine, Favlplravir and Galidesivir). We found that Noscapine-Hydroxychloroquine (Nos-Hcq) conjugate has strong binding affinity for the main protease (Mpro) of SARS-CoV-2, which performs key biological function in virus infection and progression. Nos-Hcq was analyzed through molecular dynamics simulation. The MD simulation for 100 ns affirmed the stable binding of conjugation unprecedentedly through RMSD and radius of gyration plots along with critical reaction coordinate binding free energy profile. Also, dynamical residue cross-correlation map with principal component analysis depicted the stable binding of Nos-Hcq conjugate to Mpro domains with optimal secondary structure statistics of complex dynamics. Also, we reveal the drugs with stable binding to major domains of Mpro can significantly improve the work profile of reaction coordinates, drug accession and inhibitory regulation of Mpro. The designed combinatorial therapy paves way for further prioritized in vitro and in vivo investigations for drug with robust binding against Mpro of SARS-CoV-2.

Multifaceted role of drugs: a potential weapon to outsmart Mycobacterium tuberculosis resistance by targeting its essential ThyX.

Tuberculosis (TB) is one of the prominent cause of deaths across the world and multidrug-resistant and extensively drug-resistant TB continues to pose challenges for clinicians and public health centers. The risk of death is extremely high in individuals who have compromised immune systems, HIV infection, or diabetes. Research institutes and pharmaceutical companies have been working on repurposing existing drugs as effective therapeutic options against TB. The identification of suitable drugs with multi-target affinity profiles is a widely accepted way to combat the development of resistance. Flavin-dependent thymidylate synthase (FDTS), known as ThyX, is in the class of methyltransferases and is a possible target in the discovery of novel anti-TB drugs. In this study, we aimed to repurpose existing drugs approved by Food and Drug Administration (FDA) that could be used in the treatment of TB. An integrated screening was performed based on computational procedures: high-throughput molecular docking techniques, followed by molecular dynamics simulations of the target enzyme, ThyX. After performing in silico screening using a library of 3,967 FDA-approved drugs, the two highest-scoring drugs, Carglumic acid and Mesalazine, were selected as potential candidates that could be repurposed to treat TB.Communicated by Ramaswamy H. Sarma.

Engineering a multi epitope vaccine against SARS-CoV-2 by exploiting its non structural and structural proteins.

SARS-CoV-2, the causative agent behind the ongoing pandemic exhibits an enhanced potential for infection when compared to its related family members- the SARS-CoV and MERS-CoV; which have caused similar disease outbreaks in the past. The severity of the global health burden, increasing mortality rate and the emergent economic crisis urgently demands the development of next generation vaccines. Amongst such emergent next generation vaccines are the multi-epitope subunit vaccines, which hold promise in combating deadly pathogens. In this study we have exploited immunoinformatics applications to delineate a vaccine candidate possessing multiple B and T cells epitopes by utilizing the SARS-CoV-2 non structural and structural proteins. The antigenicity potential, safety, structural stability and the production feasibility of the designed construct was evaluated computationally. Furthermore, due to the known role of human TLR-3 immune receptor in viral sensing, which facilitates host cells activation for an immune response, the vaccine construct was examined for its binding efficiency using molecular docking and molecular dynamics simulation studies, which resulted in strong and stable interactions. Finally, the immune simulation studies suggested an effective immune response on vaccine administration. Overall, the immunoinformatics analysis advocates that the proposed vaccine candidate is safe and immunogenic and therefore can be pushed as a lead for in vitro and in vivo investigations.Communicated by Ramaswamy H. Sarma.

Multiple epitope-based vaccine prediction against SARS-CoV-2 spike glycoprotein.

The global emergence of novel coronavirus disease and its rapid global expansion over a short span of time require effective countermeasures to combat it. Development of a specific vaccine can induce an optimal antibody response, thus providing immunity against it. Our study proposes a detailed and comprehensive immunoinformatic approach that can be applied to the currently available coronavirus protein data in the online server for vaccine candidate development. We have identified the receptor binding domain (RBD) of structural spike protein (S1) as a potential target for immunity against COVID- 19 infection. Epitope prediction illustrated cytotoxic T-cell epitopes, helper T-cell epitopes, and B-cell epitopes associated with the target protein. These were joined through specific linkers along with adjuvant beta-defensin located at the N-terminal to create a multi epitope subunit vaccine (MESV). The specificity in the binding of the devised vaccine candidate to the TLR-3 immune cell receptor was evaluated via molecular docking interaction studies. Good docking score combined with robust interactions in the binding cavity certified the stringency of the engineered vaccine. Molecular dynamics simulation data showed minimal variation of the root-mean square deviations (RMSDs) and root-mean-square fluctuations (RMSFs) which confirmed the interaction stability. These results obtained from various in-silico experiments indicate the potency of this vaccine candidate as a probable therapeutic agent against COVID-19. Vaccination strategies targeting conserved epitope-based immune response would be beneficial in providing cross protection across beta-coronaviruses, and such vaccines would be resistant to the ever-evolving viruses.Communicated by Ramaswamy H. Sarma.

Dual inhibition of SARS-CoV-2 spike and main protease through a repurposed drug, rutin.

The global health emergency caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to alarming numbers of fatalities across the world. So far the researchers worldwide have not been able to discover a breakthrough in the form of a potent drug or an effective vaccine. Therefore, it is imperative to discover drugs to curb the ongoing menace. In silico approaches using FDA approved drugs can expedite the drug discovery process by providing leads that can be pursued. In this report, two drug targets, namely the spike protein and main protease, belonging to structural and non-structural class of proteins respectively, were utilized to carry out drug repurposing based screening. The exposed nature of the spike protein on the viral surface along with its instrumental role in host infection and the involvement of main protease in processing of polyproteins along with no human homologue make these proteins attractive drug targets. Interestingly, the screening identified a common high efficiency binding molecule named rutin. Further, molecular dynamics simulations in explicit solvent affirmed the stable and sturdy binding of rutin with these proteins. The decreased Rg value (4 nm for spike-rutin and 2.23 nm for main protease-rutin) and stagnant SASA analysis (485 nm/S2/N in spike-rutin and 152 nm/S2/N in main protease-rutin) for protein surface and its orientation in the exposed and buried regions suggests a strong binding interaction of the drug. Further, cluster analysis and secondary structure analysis of complex trajectories validated the conformational changes due to binding of rutin.

Insights into the mutations leading to capreomycin resistance in S-adenosyl-L-methionine binding motif in TlyA from Mycobacterium tuberculosis.

Capreomycin is a second line antibiotic used for the treatment of drug resistant Tuberculosis (TB), primary reason of death from a solo infectious organism, Mycobacterium tuberculosis (M.tb). Capreomycin targets the ribosome of bacteria and is known to bind at the interface where the large and small ribosomal subunits interact in M.tb using an S-Adenosyl Methionine (SAM) dependent methyltransferase, TlyA (Rv1794). Besides the methyltransferase activity, TlyA has also been found to show substantial haemolytic activity. The dual activity of TlyA highlights its crucial role in pathogenesis and virulence of M.tb. In the present study, docking and molecular dynamics (MD) simulations were carried out to explore the impact of mutations in a conserved SAM binding motif, 90GASTG94, on the affinity of TlyA enzyme for SAM. Two already reported mutations, A91E and S92L, and the remaining wild type residues, Gly90, Thr93, Gly94 mutated to alanine were taken into consideration resulting in a total of six systems, wild type + SAM, G90A + SAM, A91E + SAM, S92L + SAM, T93A + SAM and G94A + SAM that were subjected to 100 ns MD simulations. Docking scores and MD simulations analyses revealed that in contrast to wild type, mutants reduced the affinity of SAM for TlyA with most prominent effect observed in case of alanine mutants. Mutations also led to the loss of hydrogen bond and hydrophobic interactions and large-scale movement of atoms evident from the principal component analyses indicating their destabilizing impact on TlyA. The present study gives insights into influence of mutations on binding of SAM to TlyA in M.tb and promoting capreomycin resistance.Communicated by Ramaswamy H. Sarma.

Myocilin-associated Glaucoma: A Historical Perspective and Recent Research Progress.

Glaucoma a debilitating disease, is globally the second most common kind of permanent blindness. Primary open-angle glaucoma (POAG) is its most prevalent form and is often linked with alterations in the myocilin gene (MYOC). MYOC encodes the myocilin protein, which is expressed throughout the body, but primarily in trabecular meshwork (TM) tissue in the eyes. TM is principally involved in regulating intraocular pressure (IOP), and elevated IOP is the main risk factor associated with glaucoma. The myocilin protein's function remains unknown; however, mutations compromise its folding and processing inside TM cells, contributing to the glaucoma phenotype. While glaucoma is a complex disease with various molecules and factors as contributing causes, the role played by myocilin has been the most widely studied. The current review describes the present understanding of myocilin and its association with glaucoma and aims to shift the focus toward developing targeted therapies for treating glaucoma patients with variations in MYOC.