Trofinetide for Rett Syndrome: Highlights on the Development and Related Inventions of the First USFDA-Approved Treatment for Rare Pediatric Unmet Medical Need.

Rett syndrome (RTT) is a rare disability causing female-oriented pediatric neurodevelopmental unmet medical need. RTT was recognized in 1966. However, over the past 56 years, the United States Food and Drug Administration (USFDA) has authorized no effective treatment for RTT. Recently, Trofinetide was approved by the USFDA on 10 March 2023 as the first RTT treatment. This article underlines the pharmaceutical advancement, patent literature, and prospects of Trofinetide. The data for this study were gathered from the PubMed database, authentic websites (Acadia Pharmaceuticals, Neuren Pharmaceuticals, and USFDA), and free patent databases. Trofinetide was first disclosed by Neuren Pharmaceuticals in 2000 as a methyl group containing analog of the naturally occurring neuroprotective tripeptide called glycine-proline-glutamate (GPE). The joint efforts of Acadia Pharmaceuticals and Neuren Pharmaceuticals have developed Trofinetide. The mechanism of action of Trofinetide is not yet well established. However, it is supposed to improve neuronal morphology and synaptic functioning. The patent literature revealed a handful of inventions related to Trofinetide, providing excellent and unexplored broad research possibilities with Trofinetide. The development of innovative Trofinetide-based molecules, combinations of Trofinetide, patient-compliant drug formulations, and precise MECP2-mutation-related personalized medicines are foreseeable. Trofinetide is in clinical trials for some neurodevelopmental disorders (NDDs), including treating Fragile X syndrome (FXS). It is expected that Trofinetide may be approved for treating FXS in the future. The USFDA-approval of Trofinetide is one of the important milestones for RTT therapy and is the beginning of a new era for the therapy of RTT, FXS, autism spectrum disorder (ASD), brain injury, stroke, and other NDDs.

VP37 Protein Inhibitors for Mpox Treatment: Highlights on Recent Advances, Patent Literature, and Future Directions.

Monkeypox disease (Mpox) has threatened humankind worldwide since mid-2022. The Mpox virus (MpoxV) is an example of Orthopoxviruses (OPVs), which share similar genomic structures. A few treatments and vaccines are available for Mpox. OPV-specific VP37 protein (VP37P) is a target for developing drugs against Mpox and other OPV-induced infections such as smallpox. This review spotlights the existing and prospective VP37P inhibitors (VP37PIs) for Mpox. The non-patent literature was collected from PubMed, and the patent literature was gathered from free patent databases. Very little work has been carried out on developing VP37PIs. One VP37PI (tecovirimat) has already been approved in Europe to treat Mpox, while another drug, NIOCH-14, is under clinical trial. Developing tecovirimat/NIOCH-14-based combination therapies with clinically used drugs demonstrating activity against Mpox or other OPV infections (mitoxantrone, ofloxacin, enrofloxacin, novobiocin, cidofovir, brincidofovir, idoxuridine, trifluridine, vidarabine, fialuridine, adefovir, imatinib, and rifampicin), immunity boosters (vitamin C, zinc, thymoquinone, quercetin, ginseng, etc.), and vaccines may appear a promising strategy to fight against Mpox and other OPV infections. Drug repurposing is also a good approach for identifying clinically useful VP37PIs. The dearth in the discovery process of VP37PIs makes it an interesting area for further research. The development of the tecovirimat/NIOCH-14-based hybrid molecules with certain chemotherapeutic agents looks fruitful and can be explored to obtain new VP37PI. It would be interesting and challenging to develop an ideal VP37PI concerning its specificity, safety, and efficacy.

Innovations and development of Covid-19 vaccines: A patent review.

More than 125 million confirmed cases of COVID-19 have been reported globally with rising cases in all countries since the first case was reported. A vaccine is the best measure for the effective prevention and control of COVID-19. There are more than 292 COVID-19 candidates' vaccines being developed as of July 2021 of which 184 are in human preclinical trials. A patent provides protection and a marketing monopoly to the inventor of an invention for a specified period. Therefore, vaccine developers, including Moderna, BioNTech, Janssen, Inovio, and Gamaleya also filed patent applications for the protection of their vaccines. This review aims to provide an insight into the patent literature of COVID-19 vaccines. The patent search was done using Patentscope and Espacenet databases. The results have revealed that most of the key players have patented their inventive COVID-19 vaccine. Many patent applications related to COVID-19 vaccines developed via different technologies (DNA, RNA, virus, bacteria, and protein subunit) have also been filed. The publication of a normal patent application takes place after 18 months of its filing. Therefore, many patents/patent applications related to the COVID-19 vaccine developed through different technology may come into the public domain in the coming days.

Bioinformatics analysis of rhinovirus capsid proteins VP1-4 sequences for cross-serotype vaccine development.

BACKGROUND: Rhinoviruses (RV) are associated with the development and exacerbations of asthma and chronic obstructive pulmonary disease. They've also been linked to more severe diseases like pneumonia, acute bronchiolitis, croup, and otitis media. Because of the hypervariable sequences in the same serotypes, no effective vaccine against rhinoviruses has been developed to date. With the availability of new full-length genome sequences for all RV-A and RV-B serotyped strains, this study used bioinformatics to find a suitable RV strain with the highest similarity matrices to the other strains. METHODS: The full genomic sequences of all known different RV-A and -B prototypes were downloaded from the National Centre for Biotechnology Information (NCBI) and divided into minor low-density lipoprotein receptor (LDLR) and major intercellular adhesion molecule groups (ICAM). The sequences were edited using Biological Sequence Alignment Editor, v 7.2.0 (BioEdit software) to study each capsid protein (VP1, VP2, VP3, and VP4) and analyzed using the EMBL-EBI ClustalW server and the more current Clustal Omega tool for the calculation of the identities and similarities. RESULTS: We analyzed and predicted immunogenic motifs from capsid proteins that are conserved across distinct RV serotypes using a bioinformatics technique. The amino acid sequences of VP3 were found to be the most varied, while VP4 was the most conserved protein among all RV-A and RV-B strains. Among all strains studied, RV-74 demonstrated the highest degree of homology to other strains and could be a potential genetic source for recombinant protein production. Nine highly conserved regions with a minimum length of 9-mers were identified, which could serve as potential immune targets against rhinoviruses. CONCLUSION: Therefore, bioinformatics analysis conducted in the current study has paved the way for the selection of immunogenic targets. Bioinformatically, the ideal strain's capsid protein is suggested to contain the most common RVs immunogenic sites.

Quantitative Hepatitis B e Antigen: A Better Predictor of Hepatitis B Virus DNA than Quantitative Hepatitis B Surface Antigen.

BACKGROUND: Hepatitis B surface antigen is usually secreted by infected hepatocytes in the form of subviral particles rather than infectious virions, while the hepatitis B e antigen originates from the core gene and is modified and secreted by hepatocytes into the circulation and functions as a marker of active viral replication. This study aimed to study the relationship between HBV DNA and quantitative hepatitis B surface and e antigen in Malaysian patients. METHODS: A total of 82 chronic hepatitis B patients were recruited for this study from the Hepatology Department of Selayang Hospital. Quantitative hepatitis surface and e antigen was performed retrospectively on frozen plasma using enzyme linked immunosorbent assay according to the manufacturer's instructions. Hepatitis B viral DNA was extracted from all plasma samples and quantified using real-time PCR. RESULTS: Quantitative hepatitis B surface and e antigens were found be high in 54.9% and 52.4% of the patients, respectively, while hepatitis B virus DNA level was high in 70.7%. The median of the viral load of HBV was 8,934.89 IU/mL and both hepatitis B surface and e antigens were also found to be high on average for qHBsAg (M = 5.19 IU/mL, SD ± 4. 33) and qHBeAg (M = 4.74IU/mL, SD ± 4.20), with qHBeAg being more strongly correlated to HBV DNA than qHBsAg (r = 0.893; p < 0.01). CONCLUSIONS: This study revealed HBeAg to be the most appropriate marker that correlates well with HBV DNA, thus not completely novel but confirmative, and related to the Malaysian situation.

Molecular and serological detection of occult hepatitis B virus among healthy hepatitis B surface antigen-negative blood donors in Malaysia.

BACKGROUND: Occult hepatitis B infections are becoming a major global threat, but the available data on its prevalence in various parts of the world are often divergent. OBJECTIVE: This study aimed to detect occult hepatitis B virus in hepatitis B surface antigen-negative serum using anti-HBc as a marker of previous infection. PATIENT AND METHODS: A total of 1000 randomly selected hepatitis B surface antigen-negative sera from blood donors were tested for hepatitis B core antibody and hepatitis B surface antibody using an ELISA and nested polymerase chain reaction was done using primers specific to the surface gene (S-gene). RESULTS: Of the 1000 samples 55 (5.5%) were found to be reactive, of which 87.3% (48/55) were positive for hepatitis B surface antibody, indicating immunity as a result of previous infection however, that does not exclude active infection with escaped mutant HBV. Nested PCR results showed the presence of hepatitis B viral DNA in all the 55 samples that were positive for core protein, which is in agreement with the hepatitis B surface antibody result. CONCLUSION: This study reveals the 5.5% prevalence of occult hepatitis B among Malaysian blood donors as well as the reliability of using hepatitis B core antibody in screening for occult hepatitis B infection in low endemic, low socioeconomic settings.

Design and validation of small interfering RNA on respiratory syncytial virus M2-2 gene: A potential approach in RNA interference on viral replication.

Human respiratory syncytial virus (RSV) is the leading cause of severe lower respiratory tract infection in infants and young children globally and is a significant pathogen of the elderly and immunocompromised. The M2-2 protein of respiratory syncytial virus (RSV) is particularly important in regulation of viral RNA transcription and replication that could be a potential anti-viral candidate against RSV infection. In this study, we designed and validated siRNAs that specifically target the RSV M2-2 gene. Four siRNAs targeting different regions of the M2-2 gene were designed using web tool. In-vitro evaluation of silencing effect was performed by using RSV infected Vero cell line. Viral M2-2 linked GFP recombinant plasmid was co-transfected with non-targeted siRNA, Pooled siRNA, siRNA 1, siRNA 2, siRNA 3 and siRNA 4 using synthetic cationic polymer. The silencing effect of M2-2 gene at the protein level was measured both qualitatively and quantitatively by using fluorescence microscopy and flow cytometry. Meanwhile, the silencing effect at the mRNA level was assessed by using RT-qPCR. This study showed that all four designed siRNAs can effectively and efficiently silence M2-2 gene. siRNA 2 showed the highest (98%) silencing effect on protein level and siRNA 4 with 83.1% at the mRNA level. The viral assay showed no significant cytopathic effects observed after 6days post-infection with siRNAs. In conclusion, this study showed the effectiveness of siRNA in silencing M2-2 gene both at the protein and mRNA level which could potentially be used as a novel therapeutic agent in the treatment of RSV infection. However, further study is warranted to investigate the silencing effect of M2-2 protein and inhibition of RSV infection.

An Overview of Hepatitis B Virus Surface Antigen Mutant in the Asia Pacific.

Hepatitis B virus infection is a serious health problem worldwide, and more than 350 million people are chronic carriers, constituting a major global threat. Southeast Asia and the Western Pacific have the highest levels of endemicity in the world, with an estimated seroprevalence ranging between 2% and 31%. Mutations in the hepatitis B surface antigen (HBsAg) have been reported in many parts of the world but are most common in Asian infants; such mutants have several clinical effects, such as the development of hepatocellular carcinoma. Diagnostic failures by commercial assays have reduced the diagnostic effectiveness of HBsAg detection. For example the substitution of an amino acid in the major hydrophilic region of the S gene reduces the binding of hepatitis B surface antibodies leading to immune escape. The safety of blood transfusion may be compromised by current screening tests due to escape from being neutralised by antibodies induced by HBsAg mutants, and undetectable levels of viral surface protein. Data on the epidemiology of HBsAg mutation in Asia Pacific are scant; however, this manuscript has reviewed the available information on the epidemiology of HBsAg mutation in Asia Pacific.

Antibody and immune memory persistence post infant hepatitis B vaccination.

OBJECTIVES: This study aimed to evaluate the level of hepatitis B immunity among undergraduate students 23 years after commencement of the nationwide hepatitis B childhood immunization program in Malaysia. METHODS: A total of 402 serum samples obtained from volunteer undergraduate students were screened for the presence of hepatitis B surface antibodies using qualitative ELISA. RESULTS: Results showed that 62.7% of volunteers had protective anti-hepatitis B surface antigens (≥10 IU/L), of whom 67.9% received three doses of the vaccine. The estimated post-vaccination immunity was found to be at least 20 years, indicating persistent immunity against hepatitis B and a significant association (P < 0.05) with duration of vaccination. Anamnestic response 1 month post-hepatitis B booster was 94.0% and highly significant (P < 0.01). Isolated antihepatitis B core antigen (anti-HBc) prevalence was found to be 5.0%, all having had a positive anamnestic response. CONCLUSION: Immunity after primary vaccination with hepatitis B recombinant vaccine persists for at least 20 years post-vaccination, with significant association with the number of vaccinations. Furthermore, the presence of anamnestic response to booster vaccine indicates long-lasting immunity despite decreasing antibody levels; therefore, the need for hepatitis B vaccine boosters may not be of significant benefit after complete infant vaccination.