An Updated and Focused Review on Heterocyclic Inhibitors for SARSCoV and SARS-CoV-2 3CLpro.

BACKGROUND: SARS-CoV and SARS-CoV-2 are exceedingly contagious and typically result in major respiratory illnesses (acute respiratory syndrome). The public health is facing enormous challenges across all the nations due to these newly emerging pathogens. Reliable and systematic examination of SARS-CoV and COVID-19 will assist in identifying infectious persons accurately. Based on the biological, chemical, and genetic link of SARS CoV-2 towards SARS-CoV, the recurrence of different anti-SARS-CoV natural drug molecules may be beneficial in the advancement of anti-COVID-19 herbal drug molecules. Here in this review, we evaluated SAR research that has recently been published as well as molecular docking analysis of previously synthesised compounds that have been targeted against SARS-CoV and SARS-CoV-2, respectively. This investigation might assist scientists in creating novel and revolutionary molecules that could target SAR-CoV-2. OBJECTIVES: The review highlights the heterocyclic inhibitors' ability to successfully inhibit SARSCoV and SARS-CoV-2. The meticulously described structure-activity relationship of potential SARS-CoV and SARS-CoV-2 inhibiting compounds has been addressed in this review. EVIDENCE ACQUISITION: We conducted a thorough literature assessment employing electronic databases for scientific articles highlighting potential heterocyclic inhibitors for SARS-CoVand SARSCoV- 2, published from 2010 to 2021. We recovered 415 articles, but only 220 were involved and conversed in this manuscript. The article apprehended appropriate research considering three areas: 1) SAR activity, 2) Molecular docking, and 3) Biological activity and future prospects on SARS-CoV-2. METHODS: The potential compounds with decent inhibitory activity have been discussed and reviewed along with their inhibition potential, expressed in terms of IC50 value. RESULTS: Heterocyclic scaffolds reflect an extensive spectrum of therapeutic activity and might function as an initiating concept for the designing and discovery of potential inhibitors for SARS-CoV and SARS-CoV-2 treatment. CONCLUSION: The points highlighted here may prove to be a vital tool for medicinal chemists working/ investigating more potent and efficacious scaffolds in treating SARS-CoV and SARS-CoV-2.

Hepatitis B Therapeutic Vaccine: A Patent Review.

Viral hepatitis has long been underrated as a danger to global health. The UN only recently called for worldwide action to tackle viral hepatitis and lessen the disease burden in its "2030 Agenda for Sustainable Development". Hepatitis B virus (HBV), which causes liver cirrhosis and malignancy, is a main cause of death globally. This review analyses innovative HBV therapeutic vaccine candidates for which a patent was filed between January 2010 and March 2022 and presents future improvement techniques for vaccine efficacy. Although there is a preventative vaccine for HBV infection, over 3% of people worldwide have the disease on a long-term basis and can no longer benefit from it. Most people will have chronic HBV infection for the rest of their lives once it has been diagnosed. Moreover, only a small percentage of treated patients experience a functional cure with persistent hepatitis B surface antigen reduction. A significant proportion of deaths are caused by liver cirrhosis and hepatocellular cancer, which are both caused by chronic hepatitis B infection. Hence, there is an urgent need for novel medications due to the inadequacies of the current therapies.

Small molecules as kinetoplastid specific proteasome inhibitors for leishmaniasis: a patent review from 1998 to 2021.

INTRODUCTION: Leishmaniasis is a neglected tropical infectious disease. The available limited therapeutic options for leishmaniasis are inadequate due to their poor pharmacokinetic profile, resistance, toxicity, high cost, and compliance problems. This warrants identification of new targets for the development of safer and effective anti-Leishmania therapy. The kinetoplastid specific proteasome (KSP) is a novel validated target to develop drugs against leishmaniasis. AREA COVERED: This review focuses on all the published patent applications and granted patents related to the studied small molecules as KSP inhibitors (KSPIs) against Leishmania from 1998 to 31 December 2021. EXPERT OPINION: A little amount of work has been done on KSPIs, but the study results are quite encouraging. LXE408 and GSK3494245 are two KSPIs in different phases of clinical trials. Some other small molecules have also shown KSP inhibitory potential, but they are not in clinical trials. The KSPIs are promising next-generation orally active patient compliant drugs against kinetoplastid diseases, including leishmaniasis. However, the main challenge to discover the KSPIs will be the resistance development and their selectivity against the proteasome of eukaryotic cells.

Discovery, Development, and Patent Trends on Molnupiravir: A Prospective Oral Treatment for COVID-19.

The COVID-19 pandemic needs no introduction at present. Only a few treatments are available for this disease, including remdesivir and favipiravir. Accordingly, the pharmaceutical industry is striving to develop new treatments for COVID-19. Molnupiravir, an orally active RdRp inhibitor, is in a phase 3 clinical trial against COVID-19. The objective of this review article is to enlighten the researchers working on COVID-19 about the discovery, recent developments, and patents related to molnupiravir. Molnupiravir was originally developed for the treatment of influenza at Emory University, USA. However, this drug has also demonstrated activity against a variety of viruses, including SARS-CoV-2. Now it is being jointly developed by Emory University, Ridgeback Biotherapeutics, and Merck to treat COVID-19. The published clinical data indicate a good safety profile, tolerability, and oral bioavailability of molnupiravir in humans. The patient-compliant oral dosage form of molnupiravir may hit the market in the first or second quarter of 2022. The patent data of molnupiravir revealed its granted compound patent and process-related patent applications. We also anticipate patent filing related to oral dosage forms, inhalers, and a combination of molnupiravir with marketed drugs like remdesivir, favipiravir, and baricitinib. The current pandemic demands a patient compliant, safe, tolerable, and orally effective COVID-19 treatment. The authors believe that molnupiravir meets these requirements and is a breakthrough COVID-19 treatment.

Innovations and Patent Trends in the Development of USFDA Approved Protein Kinase Inhibitors in the Last Two Decades.

Protein kinase inhibitors (PKIs) are important therapeutic agents. As of 31 May 2021, the United States Food and Drug Administration (USFDA) has approved 70 PKIs. Most of the PKIs are employed to treat cancer and inflammatory diseases. Imatinib was the first PKI approved by USFDA in 2001. This review summarizes the compound patents and the essential polymorph patents of the PKIs approved by the USFDA from 2001 to 31 May 2021. The dates on the generic drug availability of the PKIs in the USA market have also been forecasted. It is expected that 19 and 48 PKIs will be genericized by 2025 and 2030, respectively, due to their compound patent expiry. This may reduce the financial toxicity associated with the existing PKIs. There are nearly 535 reported PKs. However, the USFDA approved PKIs target only about 10-15% of the total said PKs. As a result, there are still a large number of unexplored PKs. As the field advances during the next 20 years, one can anticipate that PKIs with many scaffolds, chemotypes, and pharmacophores will be developed.

Trends in the development of remdesivir based inventions against COVID-19 and other disorders: A patent review.

The development of remdesivir has been a breakthrough for COVID-19 treatment. It has been approved in about 50 countries, including Saudi Arabia, since 2020. The generic structure of remdesivir was first disclosed in 2009. This patent review summarizes the remdesivir based inventions to treat/prevent COVID-19 and other disorders from 2009 to May 16, 2021, emphasizing the patents related to medical and pharmaceutical sciences. The primary patents/patent applications of remdesivir are related to its compositions, new combinations with other therapeutic agents, delivery systems, and new indications. The inventive combinations have displayed synergistic effects against COVID-19, whereas the delivery systems/compositions have improved patient compliance. The inventions related to new indications of remdesivir to treat Ebola, hepatitis, idiopathic pulmonary fibrosis, diabetic nephropathy, and cardiovascular complications enhance its therapeutic area. Many new innovative combinations and delivery systems of remdesivir are anticipated to provide better treatment for COVID-19.

Cell Culture, Technology: Enhancing the Culture of Diagnosing Human Diseases.

Cell culture involves a complex of processes of cell isolation from their natural environment (in vivo) and subsequent growth in a controlled environmental artificial condition (in vitro). Cells from specific tissues or organs are cultured as short term or established cell lines which are widely used for research and diagnosis, most specially in the aspect of viral infection, because pathogenic viral isolation depends on the availability of permissible cell cultures. Cell culture provides the required setting for the detection and identification of numerous pathogens of humans, which is achieved via virus isolation in the cell culture as the "gold standard" for virus discovery. In this review, we summarized the views of researchers on the current role of cell culture technology in the diagnosis of human diseases. The technological advancement of recent years, starting with monoclonal antibody development to molecular techniques, provides an important approach for detecting presence of viral infection. They are also used as a baseline for establishing rapid tests for newly discovered pathogens. A combination of virus isolation in cell culture and molecular methods is still critical in identifying viruses that were previously unrecognized. Therefore, cell culture should be considered as a fundamental procedure in identifying suspected infectious viral agent.

Isolated hepatitis B core antibody positive among vaccinated cohort in Malaysia.

BACKGROUND AND OBJECTIVES: Hepatitis B core antibodies (anti-HBc) are detected in almost every patient with previous exposure to hepatitis B virus (HBV). However, with this marker alone, one cannot understand the activity of the disease; therefore, this study aimed to identify the implication of isolated hepatitis B core antibody and evaluate the effect of hepatitis B vaccine booster in isolated anti-HBc among adults who received the HBV vaccine as infants. DESIGN AND SETTINGS: A prospective cohort study of vaccinated undergraduate students of University Putra Malaysia. PATIENTS AND METHODS: A total of 408 undergraduate students who received infant hepatitis B vaccination volunteered for this study; 5 mL of venous blood was taken from the volunteers. Hepatitis B surface antigen (HBsAg) and core antibodies were tested using a commercially available enzyme-linked immunosorbent assay kit according to the manufacturer's instructions (DRG international Inc., USA). Molecular detection of hepatitis B viral DNA was performed using nested polymerase chain reaction. RESULTS: The prevalence of isolated anti-HBc among the vaccinated cohort was found to be 5.0%, out of which 80% had a hepatitis B surface antibodies (anti-HBs) titer higher than 10 IU/L, while 20% had less than 10 IU/L anti-HBs titer. All the anti-HBc positivesubjects had detectable hepatitis B viral DNA in their serum. Anamnestic response was found to be 100% among isolated anti-HBc with negative antibody. CONCLUSION: Isolated anti-HBc developed protective levels of anti-HBs after a single dose of recombinant hepatitis B vaccination. HBV DNA was detected in all isolated anti-HBc indicating occult chronic HBV infection with undetectable HBsAg.