20 research outputs found
Exploring combined verses single mode of inhibition of Mycobacterium Tuberculosis RNA polymerase as a therapeutic intervention to overcome drug resistance challenges: atomistic perspectives.
Masters Degree. University of KwaZulu-Natal, Westville.The impact of Rifampin resistance on the overall global epidemic of antimicrobial resistance has
become very prominent in recent years and is eventually stifling current efforts being made to control
tuberculosis drug resistance. Rifampin resistance has significantly contributed to making TB the
leading cause of morbidity from an infectious disease globally. The RNA polymerase of
Mycobacterium tuberculosis has been extensively explored as a therapeutic target for Rifampin
resistance with recent studies exploring synergistic inhibition as an effective approach, by combining
Rifampin and other drugs in the TB drug resistance. Apart from the paucity of data elucidating the
structural mechanism of action of the synergistic interaction between Rifampin and DAAPI, previous
studies did not also utilize the X-ray crystal structure of Mtb RNAP due its unavailability.
This thesis used advanced computational tools to unravel molecular insights into the suppression of
the emergence of resistance to Rifampin by a novel NĪ±-aroyl-N-aryl-phenylalaninamides (AAPI)
prototype inhibitor, DAAPI, co-bound to Mtb RNAP with Rifampin. Our studies revealed co-binding
induced a stable Mtb RNAP protein structure, increased the degree of compactness of binding site
residues around Rifampin and subsequently improved the binding affinity of Rifampin.
Studies in this thesis further provide an atomistic mechanism behind Rifampin resistance when the
recently resolved crystal structure of Mycobacterium tuberculosis RNA polymerase is subjected to a
single active site mutation. We also identified and rationalized the structural interplay of this single
active site mutation upon co-binding of Rifampin with the novel inhibitor, DAAPI. Our findings
report that the mutation distorted the overall conformational landscape of Mycobacterium
tuberculosis RNA polymerase, resulting in a reduction of binding affinity of Rifampin and an overall
shift in the residue interaction network of Mycobacterium tuberculosis RNA polymerase and upon
single binding. Interestingly, co-binding with DAAPI, though impacted by the mutation exhibited
improved Rifampin binding interactions amidst a distorted residue interaction network.
Findings establish a structural mechanism by which the novel inhibitor DAAPI stabilizes
Mycobacterium tuberculosis RNA polymerase upon co-binding with Rifampin, thus suppressing
Rifampin resistance. We also provide vital conformational dynamics and structural mechanisms of
mutant enzyme-single ligand and mutant enzyme-dual ligand interactions which could potentially
shift the current therapeutic protocol of TB infections, thus aiding in the design of novel
Mycobacterium tuberculosis RNA polymerase inhibitors with improved therapeutic features against
the mutant proteins
Computer-aided approaches in drug design: the exigent way forward: dynamic perspectives into the mechanistic activities of small molecule inhibitors toward antiviral, antitubercular and anticancer therapeutic interventions.
Doctoral Degree. University of KwaZulu-Natal, Durban.The crucial role of CADD in the drug design process is now indisputable and has proven over the
years that it can accelerate the discovery potential drug candidates while reducing the associated
cost. Using knowledge and information about biological target or knowledge about a ligand with
proven bioactivity, CADD, and its techniques can influence various drug discovery pipeline stages.
The ability CADD approaches to elucidate drug-target interactions at the atomistic level allows
for investigations of the mechanism of drugs' actions, revealing atomistic insights that influence
drug design and improvement. CADD approaches also seek to augment traditional in vitro and in
vivo experimental techniques and not replace them since CADD approaches can also allow
modeling complex biological processes that hitherto seemed impossible to explore using
experimental methods.
According to the World Health Organization (WHO), featuring prominently in the top ten causes
of death are cancer, lower respiratory tract infection, tuberculosis (TB), and viral infections such
as HIV/AIDS. Collectively, these diseases are of global health concerns, considering a large
number of associated deaths yearly. Over the years, several therapeutic interventions have been
employed to treat, manage, or cure these diseases, including chemotherapy, surgery, and
radiotherapy. Of these options, small molecule inhibitors have constituted an integral component
in chemotherapy, thereby undoubtedly playing an essential role in patient management.
Although significant success has been achieved using existing therapeutic approaches, the
emergence of drug resistance and the challenges of associated adverse side effects has prompted
the need for the drug design processes against these diseases to remain innovative, including
combining existing drugs and establishing improved therapeutic options that could overcome
resistance while maintaining minimal side effects to patients. Therefore, an exploration of drug
target interactions towards unraveling mechanisms of actions as performed in the reports in this
thesis are relevant since the molecular mechanism provided could form the basis for the design
and identification of new therapeutic agents, improvement of the therapeutic activity of existing
drugs, and also aid in the development of novel therapeutic strategies against these diseases of
global health concern.
Therefore the studies in this thesis employed CADD approaches to investigates molecular
mechanisms of actions of novel therapeutic strategies directed towards some crucial therapeutics
implicated in viral infections, tuberculosis, and cancer. Therapeutic targets studied included;
SARS-CoV-2 RNA dependent RNA polymerase (SARS-CoV-2 RdRp), Human Rhinovirus B14
(HRV-B14) and human N-myristoyltransferases in viral infections, Dihydrofolate reductase
(DHFR) and Flavin-dependent thymidylate synthase (FDTS) in TB, human variants of TCRCD1d,
and Protein Tyrosine Phosphatase Receptor Zeta (PTPRZ) in cancer.
The studies in this thesis is divided into three domains and begins with a thorough review of the
concept of druggability and drug-likeness since the crux of the subsequent reports revolved around
therapeutic targets and their inhibitions by small molecule inhibitors. This review highlights the
principles of druggability and drug-likeness while detailing the recent advancements in drug
discovery. The review concludes by presenting the different computational, highlighting their
reliability for predictive analysis.
In the first domain of the research, we sought to unravel the inhibitory mechanism of some small
molecule inhibitors against some therapeutic targets in viral infections by explicitly focusing on
the therapeutic targets; SARS-CoV-2 RdRp, HRV-B14, and N-myristoyltransferase.
Therapeutic targeting of SARS-CoV-2 RdRp has been extensively explored as a viable approach
in the treatment of COVID-19. By examining the binding mechanism of Remdesivir, which
hitherto was unclear, this study sought to unravel the structural and conformational implications
on SARS-CoV-2 RdRp and subsequently identify crucial pharmacophoric moieties of Remdesivir
required for its inhibitory potency. Computational analysis showed that the modulatory activity of
Remdesivir is characterized by an extensive array of high-affinity and consistent molecular
interactions with specific active site residues that anchor Remdemsivir within the binding pocket
for efficient binding. Results also showed that Remdesivir binding induces minimal individual
amino acid perturbations, subtly interferes with deviations of C-Ī± atoms, and restricts the
systematic transition of SARS-CoV-2 RdRp from the āburiedā hydrophobic region to the āsurface exposedā
hydrophilic region. Based on observed high-affinity interactions with SARS-CoV-2
RdRp, a pharmacophore model was generated, which showcased the crucial functional moieties
of Remdesivir. The pharmacophore was subsequently employed for virtual screening to identify
potential inhibitors of SARS-CoV-2 RdRp. The structural insights and the optimized
pharmacophoric model provided would augment the design of improved analogs of Remdesivir
that could expand treatment options for COVID-19.
The next study sought to explore the therapeutic targeting of human rhinoviruses (HRV) amidst
challenges associated with the existence of a wide variety of HRV serotypes. By employing
advanced computational techniques, the molecular mechanism of inhibition of a novel
benzothiophene derivative that reportedly binds HRV-B14 was investigated. An analysis of the
residue-residue interaction profile revealed of HRV upon the benzothiophene derivative binding
revealed a distortion of the hitherto compacted and extensively networked HRV structure. This
was evidenced by the fewer inter-residue hydrogen bonds, reduced van der Waals interactions, and
increased residue flexibility. However, a decrease in the north-south wall's flexibility around the
canyon region also suggested that the benzothiophene derivative's binding impedes the ābreathing
motionā of HRV-B14; hence its inhibition.
The next study in the first domain of the research investigated the structural and molecular
mechanisms of action associated with the dual inhibitory activity of IMP-1088. This novel
compound reportedly inhibits human N-myristoyltransferase subtypes 1 and 2 towards common
cold therapy. This is because it has emerged that the pharmacological inhibition of Nmyristoyltransferase
is an efficient non-cytotoxic strategy to completely thwart the replication
process of rhinovirus toward common cold treatment. Using augmentative computational and
nanosecond-based analyses, findings of the study revealed that the steady and consistent
interactions of IMP-1088 with specific residues; Tyr296, Phe190, Tyr420, Leu453, Gln496,
Val181, Leu474, Glu182, and Asn246, shared within the binding pockets of both HNMT subtypes,
in addition to peculiar structural changes account for its dual inhibitory potency. Findings thus
unveiled atomistic and structural perspectives that could form the basis for designing novel dualacting
inhibitors of N-myristoyltransferase towards common cold therapy.
In the second domain of the research, the mechanism of action of some small molecule inhibitors
against DHFR, FDTS, and Mtb ATP synthase in treating tuberculosis is extensively investigated
and reportedly subsequently.
To begin with, the dual therapeutic targeting of crucial enzymes in the folate biosynthetic pathway
was explored towards developing novel treatment methods for TB. Therefore, the study
investigated the molecular mechanisms and structural dynamics associated with dual inhibitory
activity of PAS-M against both DHFR and FDTS, which hitherto was unclear. MD simulations
revealed that PAS-M binding towards DHFR and FDTS is characterized by a recurrence of strong
conventional hydrogen bond interactions between a peculiar site residue the 2-aminov
decahydropteridin-4-ol group of PAS-M. Structural dynamics of the bound complexes of both
enzymes revealed that, upon binding, PAS-M is anchored at the entrance of hydrophobic pockets
by a strong hydrogen bond interaction while the rest of the structure gains access to deeper
hydrophobic residues to engage in favorable interactions. Further analysis of atomistic changes of
both enzymes showed increased C-Ī± atom deviations and an increase C-Ī± atoms radius of gyration
consistent with structural disorientations. These conformational changes possibly interfered with
the enzymes' biological functions and hence their inhibition as experimentally reported.
Additionally, in this domain, the therapeutic targeting of the ATP machinery of Mtb by
Bedaquiline (BDQ) was explored towards unravelling the structures and atomistic perspectives
that account for the ability of BDQ to selectively inhibits mycobacterial F1Fo-ATP synthase via its
rotor c-ring. BDQ is shown to form strong interaction with Glu65B and Asp32B and, consequently,
block these residues' role in proton binding and ion. BDQ binding was also revealed to impede the
rotatory motion of the rotor c-ring by inducing a compact conformation on the ring with its bulky
structure. Complementary binding of two molecules of BDQ to the rotor c-ring, proving that
increasing the number of BDQ molecule enhances inhibitory potency.
The last study in this research domain investigated the impact of triple mutations (L59V, E61D,
and I66M) on the binding of BDQ to Mtb F1F0 ATP-synthase. The study showed that the
mutations significantly impacted the binding affinity of BDQ, evidenced by a decrease in the
estimated binding free energy (ĪG). Likewise, the structural integrity and conformational
architecture of F1F0 ATP-synthase was distorted due to the mutation, which could have interfered
with the binding of BDQ.
The third domain of the research in this thesis investigated some small molecule inhibitors'
inhibitory mechanism against some therapeutic targets in cancer, specifically PTPRZ and hTCRvi
CD1d. Studies in the third domain of the research in the thesis began with the investigation of the
investigation of the inhibitory mechanism of NAZ2329, an allosteric inhibitor of PTPRZ, by
specifical investigating its binding effect on the atomic flexibility of the WPD-loop. Having been
established as crucial determinant of the catalytic activity of PTPRZ an implicated protein in
glioblastoma cells, its successfully therapeutic modulation could present a viable treatment option
in glioblastoma. Structural insights from an MD simulation revealed that NAZ2329 binding
induces an open conformation of the WPD-loop which subsequently prevents the participation of
the catalytic aspartate of PTPRZ from participating in catalysis hence inhibiting the activity of
PTPRZ. A pharmacophore was also created based of high energy contributing residues which
highlighted essential moieties of NAZ2329 and could be used in screening compound libraries for
potential inhibitors of PTPRZ.
A second study in this domain sought to explore how structural modification could improve a
therapeutic agent's potency from an atomistic perspective. This study was based on an earlier report
in which the incorporation of a hydrocinnamoyl ester on C6āā and C4-OH truncation of the
sphingoid base of KRN7000 generated a novel compound AH10-7 high therapeutic potency and
selectivity in human TCR-CD1d and subsequently results in the activation of invariant natural
killer T cells (iNKT). The hydrocinnamoyl ester moiety was shown to engage in high-affinity
interactions, possibly accounting for the selectivity and higher potency of AH10-7. Molecular and
structural perspectives provided could aid in the design of novel Ī±-GalCer derivatives for cancer
immunotherapeutics.
Chapter 3 provides theoretical insights into the various molecular modeling tools and techniques
employed to investigate the various conformational changes, structural conformations, and the
associated mechanism of inhibitions of the studied inhibitors towards viral, tuberculosis, and
cancer therapy.
Chapter 4 provided sufficient details on druggability and drug-likeness principles and their recent
advancements in the drug discovery field. The study also presents the different computational tools
and their reliability of predictive analysis in the drug discovery domain. It thus provides a
comprehensive guide for computational-oriented drug discovery research.
Chapter 5 provides an understanding of the binding mechanism of Remdesivir, providing structural
and conformational implications on SARS-CoV-2 RdRp upon its binding and identifying its
crucial pharmacophoric moieties.
Chapter 6 explains the mechanism of inhibition of a novel benzothiophene derivative, revealing
its distortion of the native extensively networked and compact residue profile.
Chapter 7 unravels molecular and structural bases behind this dual inhibitory potential of the novel
inhibitor IMP-1088 toward common cold therapy using augmentative computational and
cheminformatics methods. The study also highlights the pharmacological propensities of IMP-
1088.
Chapter 8 unravels the molecular mechanisms and structural dynamics of the dual inhibitory
activity of PAS-M towards DHFR and FDTS.
Chapter 9 reports the structural dynamics and atomistic perspectives that account for the reported
ability of BDQ to halt the ion shuttling ability of mycobacterial c-ring.
Chapter 10 presents the structural dynamics and conformational changes that occur on Mtb F1F0
ATP-synthase binding as a result of the triple mutations using molecular dynamics simulations,
free energy binding, and residue interaction network (RIN) analyses.
Chapter 11 explored the impact of NAZ2329, a recently identified allosteric inhibitor of Protein
Tyrosine Phosphatase Receptor Zeta (PTPRZ), on the atomic flexibility of the WPD-loop, an
essential loop in the inhibition of PTPRZ. The study also presents the drug-likeness of NAZ2329
using in silico techniques and its general inhibitory mechanism.
Chapter 12 provides atomistic insights into the structural dynamics and selective mechanisms of
AH10-7 for human TCR-CD1d towards activating iNKT cells.
The studies in this thesis collectively present a thorough and comprehensive in silico perspective
that characterizes the pharmacological inhibition of some known therapeutic targets in viral
infections, tuberculosis, and cancer. The augmentative integration of computational methods to
provide structural insights could help design highly selective inhibitors of these therapeutic targets.
Therefore, the findings presented are fundamental to the design and development of next generation
lead compounds with improved therapeutic activities and minimal toxicities
Assessment of urogenital schistosomiasis among basic school children in selected communities along major rivers in the central region of Ghana
Introduction: urogenital schistosomiasis affects school-aged children with impacts on health, growth, and cognitive development. Basic schools along active water bodies have a possibility of a high infection among the children.
Methods: we performed a school-based cross-sectional assessment of urogenital schistosomiasis among children in four selected rural communities along major rivers in the central region of Ghana. Three hundred and nine (309) basic school children class 1 to junior high school (JHS) 3 were recruited. Sociodemographic data and information on behavioral influences were collected with a structured written questionnaire. Laboratory examinations were conducted on fresh urine samples. Descriptive statistics and cross-tabulations with measures of association between variables, adjusted and unadjusted logistic regression analysis were performed on measured variables.
Results: we recorded a 10.4% prevalence of urogenital schistosomiasis. Schools in communities along the Kakum river recorded the highest disease burden (65.6%). The odds of infection among pupils who engage in irrigation activities were 4 folds more than those who do not engage in irrigation activities (adjusted odds ratio (aOR) (95%CI): 4.3 (1.6-12.1), P-value=0.005). Pupils of caregivers who resort to self-medication using local herbal concoctions had 14-fold more odds of infection compared to those who visit the health facility (aOR (95%CI): 14.4 (1.4-143.1), P-value=0.006).
Conclusion: poor health-seeking behaviors and lack of access to health facilities influenced the disease proportion among the children in these endemic communities
Dual-Target <i>Mycobacterium tuberculosis</i> Inhibition: Insights into the Molecular Mechanism of Antifolate Drugs
The escalating prevalence of drug-resistant strains of Mycobacterium tuberculosis has posed a significant challenge to global efforts in combating tuberculosis. To address this issue, innovative therapeutic strategies are required that target essential biochemical pathways while minimizing the potential for resistance development. The concept of dual targeting has gained prominence in drug discovery against resistance bacteria. Dual targeting recognizes the complexity of cellular processes and disrupts more than one vital pathway, simultaneously. By inhibiting more than one essential process required for bacterial growth and survival, the chances of developing resistance are substantially reduced. A previously reported study investigated the dual-targeting potential of a series of novel compounds against the folate pathway in Mycobacterium tuberculosis. Expanding on this study, we investigated the predictive pharmacokinetic profiling and the structural mechanism of inhibition of UCP1172, UCP1175, and UCP1063 on key enzymes, dihydrofolate reductase (DHFR) and 5-amino-6-ribitylamino-2,4(1H,3H)-pyrimidinedione 5ā²-phosphate reductase (RV2671), involved in the folate pathway. Our findings indicate that the compounds demonstrate lipophilic physiochemical properties that promote gastrointestinal absorption, and may also inhibit the drug-metabolizing enzyme, cytochrome P450 3A4, thus enhancing their biological half-life. Furthermore, key catalytic residues (Serine, Threonine, and Aspartate), conserved in both enzymes, were found to participate in vital molecular interactions with UCP1172, which demonstrated the most favorable free binding energies to both DHFR and RV2671 (ā41.63 kcal/mol, ā48.04 kcal/mol, respectively). The presence of characteristic loop shifts, which are similar in both enzymes, also indicates a common inhibitory mechanism by UCP1172. This elucidation advances the understanding of UCP1172ās dual inhibition mechanism against Mycobacterium tuberculosis.</i
Modelling the Transitioning of SARS-CoV-2 nsp3 and nsp4 Lumenal Regions towards a More Stable State on Complex Formation
During coronavirus infection, three non-structural proteins, nsp3, nsp4, and nsp6, are of great importance as they induce the formation of double-membrane vesicles where the replication and transcription of viral gRNA takes place, and the interaction of nsp3 and nsp4 lumenal regions triggers membrane pairing. However, their structural states are not well-understood. We investigated the interactions between nsp3 and nsp4 by predicting the structures of their lumenal regions individually and in complex using AlphaFold2 as implemented in ColabFold. The ColabFold prediction accuracy of the nsp3ānsp4 complex was increased compared to nsp3 alone and nsp4 alone. All cysteine residues in both lumenal regions were modelled to be involved in intramolecular disulphide bonds. A linker region in the nsp4 lumenal region emerged as crucial for the interaction, transitioning to a structured state when predicted in complex. The key interactions modelled between nsp3 and nsp4 appeared stable when the transmembrane regions of nsp3 and nsp4 were added to the modelling either alone or together. While molecular dynamics simulations (MD) demonstrated that the proposed model of the nsp3 lumenal region on its own is not stable, key interactions between nsp and nsp4 in the proposed complex model appeared stable after MD. Together, these observations suggest that the interaction is robust to different modelling conditions. Understanding the functional importance of the nsp4 linker region may have implications for the targeting of double membrane vesicle formation in controlling coronavirus infection
Normal Non-HDL Cholesterol, Low Total Cholesterol, and HDL Cholesterol Levels in Sickle Cell Disease Patients in the Steady State: A Case-Control Study of Tema Metropolis
Background. Abnormal lipid homeostasis in sickle cell disease (SCD) is characterized by defects in plasma and erythrocyte lipids and may increase the risk of cardiovascular disease. This study assessed the lipid profile and non-HDL cholesterol level of SCD patients. Methods. A hospital-based cross-sectional study was conducted in 50 SCD patients, in the steady state, aged 8ā28 years, attending the SCD clinic, and 50 healthy volunteers between the ages of 8ā38 years. Serum lipids were determined by enzymatic methods and non-HDL cholesterol calculated by this formula: non-HDL-C = TC-HDL-C. Results. Total cholesterol (TC) (p=0.001) and high-density lipoprotein cholesterol (HDL-C) (p<0.0001) were significantly decreased in cases compared to controls. The levels of non-HDL-C, low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) were similar among the participants. The levels of decrease in TC and HDL were associated with whether a patient was SCD-SS or SCD-SC. Systolic blood pressure and diastolic blood pressure were each significantly associated with increased VLDL [SBP, p=0.01, OR: 0.74 (CI: 0.6ā0.93); DBP, p=0.023, OR: 1.45 (CI: 1.05ā2.0)]. Conclusion. Dyslipidemia is common among participants in this study. It was more pronounced in the SCD-SS than in SCD-SC. This dyslipidemia was associated with high VLDL as well as increased SBP and DBP
In silico identification of potential PvFKBP35 inhibitors from Entadrophragma angolense Limonoids extracts as antimalarial agents
Plasmodium species, which are spread by female Anopheles mosquitoes, are responsible for malaria. Out of the five major Plasmodium species, Plasmodium falciparum and Plasmodium vivax are the most deadly and invasive species responsible for 99.7% and 75% of malaria cases in Africa and America respectively. Despite the invasive nature of malaria, the Plasmodium parasite continues to develop resistance to current drugs. It is therefore imperative to come up with new therapeutics to combat malaria. Previous studies have reported that Limonoids from the Meliaceae family possess antimalarial properties. This study therefore aims at employing computational approaches to identify potential antimalarial Limonoids by targeting PvFKBP35. PvFKBP35 has been reported to be a suitable target for antimalarial therapeutics as it is involved in various physiological activities including transcription, protein stability and folding. Molecular docking, Molecular Dynamics simulation and Molecular Mechanics-Poisson Boltzmann Surface Area calculation were employed to identify the potential leads. Sixteen [16] Limonoids extracted from the bark of the stem of Entadrophragma angolense were virtually screened against PvFKPB35. The top hit compounds were subjected to 500 ns Molecular Dynamics simulation and Molecular Mechanics ā Poisson Boltzmann Surface Area calculations to examine their stability and free binding energy. Two potential leads, compounds 1 and 11 with binding energies ā6.3 and ā5.4Ā kcal/mol respectively were identified. The potential leads in complexed with PvFKBP35 had an average root mean square deviation of 1.18Ā Ā±Ā 0.19Ā Ć
and 3.12Ā Ā±Ā 0.60Ā Ć
, indicating their stability. Solvent Accessible Surface Area was utilized to predict the penetrative ability of the compounds into the binding pocket. Average Solvent Accessible Surface Area values of 327.88Ā Ā±Ā 47.54 A2, 402.18Ā Ā±Ā 39.81 A2 were obtained for compounds 1 and 11 respectively. ADMET estimations of compounds 1 and 11 predicted them to be druglike and do not violate Lipinski's rule of five. Compounds 1 and 11 need be tested in vitro to validate their antimalarial activity although they were predicted to be antiprotozoal with Pa values 0.207 and 0.162. These compounds can then serve as the scaffold for the design of novel antimalarial therapeutics
Influenza Viruses: Harnessing the Crucial Role of the M2 Ion-Channel and Neuraminidase toward Inhibitor Design
As a member of the Orthomyxoviridae family of viruses, influenza viruses (IVs) are known causative agents of respiratory infection in vertebrates. They remain a major global threat responsible for the most virulent diseases and global pandemics in humans. The virulence of IVs and the consequential high morbidity and mortality of IV infections are primarily attributed to the high mutation rates in the IVsā genome coupled with the numerous genomic segments, which give rise to antiviral resistant and vaccine evading strains. Current therapeutic options include vaccines and small molecule inhibitors, which therapeutically target various catalytic processes in IVs. However, the periodic emergence of new IV strains necessitates the continuous development of novel anti-influenza therapeutic options. The crux of this review highlights the recent studies on the biology of influenza viruses, focusing on the structure, function, and mechanism of action of the M2 channel and neuraminidase as therapeutic targets. We further provide an update on the development of new M2 channel and neuraminidase inhibitors as an alternative to existing anti-influenza therapy. We conclude by highlighting therapeutic strategies that could be explored further towards the design of novel anti-influenza inhibitors with the ability to inhibit resistant strains
Influenza Viruses: Harnessing the Crucial Role of the M2 Ion-Channel and Neuraminidase toward Inhibitor Design
As a member of the Orthomyxoviridae family of viruses, influenza viruses (IVs) are known causative agents of respiratory infection in vertebrates. They remain a major global threat responsible for the most virulent diseases and global pandemics in humans. The virulence of IVs and the consequential high morbidity and mortality of IV infections are primarily attributed to the high mutation rates in the IVsā genome coupled with the numerous genomic segments, which give rise to antiviral resistant and vaccine evading strains. Current therapeutic options include vaccines and small molecule inhibitors, which therapeutically target various catalytic processes in IVs. However, the periodic emergence of new IV strains necessitates the continuous development of novel anti-influenza therapeutic options. The crux of this review highlights the recent studies on the biology of influenza viruses, focusing on the structure, function, and mechanism of action of the M2 channel and neuraminidase as therapeutic targets. We further provide an update on the development of new M2 channel and neuraminidase inhibitors as an alternative to existing anti-influenza therapy. We conclude by highlighting therapeutic strategies that could be explored further towards the design of novel anti-influenza inhibitors with the ability to inhibit resistant strains