Special Issue:
Challenges and Opportunities in Pharmacogenomics
Fuhai LI
The Ohio State University, Columbus, OH, USA
Abstract
Large-scale data sets of cancer patients have been being generated due to the significantly reduced cost of sequencing full genome of individual patients using the Next Generation Sequencing (NGS) technology. Comprehensive genomics data analysis revealed the diverse dysfunctional biomarkers of individual cancer patients, which are believed to be responsible for heterogeneous drug response. Thus precision medicine is becoming popular that aims to find the optimal treatments for individual patients based on their genomics profiling data. However, it is challenging to interpret the complicated and distinct genome mutation and variation patterns, and associate them to optimal treatments. Though a set of approaches and data resources have been reported to reposition FDA approved drugs and investigational drugs for specific diseases, novel and sophisticated computational approaches are needed urgently to reposition drugs for cancer subtypes or individual patients. In this study, some widely used computational approaches and pharmacogenomics data resources for repositioning optimal drugs are introduced and discussed, which aims to provide a general overview of the genomic data-driven drug repositioning, and help readers understand the topic conveniently.
Eduardo Rodriguez Yunta
Ph.D., University of Chile
Abstract
This study reviews ethical issues encountered in the literature about the use of pharmacogenomics in personalized medicine. Data gathered from Medline, Scopus, and Scielo were grouped as issues belonging to the application of the four bioethical principles. Autonomy: informed consent with vulnerable populations, consent for biobanks, changes in the physician-patient relationship, safeguarding confidentiality; non-malifecence: risks of stigmatization and discrimination, risks in clinical trials; beneficence: risk/benefit assessment in favor of benefit; and justice: pharmacogenetic tests and public health interests, equity concerns. Issues discussed were: reasons in favor and against returning research results from genomic and pharmacogenetic testing, enhancing the participation of vulnerable populations, and the reconsideration of respect for autonomy from a viewpoint too individualistic to a communal perspective since personal reality is constructed in relation to many significant others.
Stephen Eugene Fry
Fry Laboratories, LLC
Abstract
The advent of high throughput human DNA sequencing capability has allowed a crossover for sequencing infectious diseases. The same technologies that allow us to query the human genome for cancer mutations, pharmacogenomics, and inherited genetic errors now allow a more in-depth analysis of human samples for evidence of infectious disease. Next Generation DNA sequencing (NGS) for infectious disease holds the promise of accuracy with greater sensitivity and specificity than culture, serologic and PCR methods. NGS allows for better discrimination between strains, species, detection of novel variants and new organisms, detection of an ever-growing array of uncultivable organisms, and the ability to detect eukaryotes that were previously undetectable. NGS also may soon provide the ability to determine drug resistance and sensitivity information. The following describes the Rapid Infectious Disease Identification System (RIDI™) and its practical use. Application of the RIDI™ system is discussed in four case reports with patients suffering from chronic malaise, rheumatoid arthritis, osteoarthritis, and chronic fatigue syndrome.
Oscar Cobar
Pharmacogenomics and Nutrigenomics Research Group, School of Chemical Sciences and Pharmacy, University of San Carlos, Guatemala; Biomedical Sciences Ph.D. Program, School of Medical Sciences, University of San Carlos, Guatemala.
Stella Cobar
School of Chemical Sciences and Pharmacy, University of San Carlos, Guatemala.
Abstract
Background: JN.1 (BA.2.86.1.1) has become the dominant strain in the U.S. at the end of 2023 according to the U.S. Centers for Disease Control and Prevention. The strain is a descendant of EG.5 family that was identified in China in February 2023 and was first detected in the United States in April 2023. JN.1* SARSCoV2 lineages: JN.1 (BA.2.86.1.1), JN.1.1, JN.1.1.1, JN.1.2, JN.1.3 and recombinants XDD (EG.5.1.1/JN.1), XDK (XBB*/JN.1.1.1). There is only a single change between JN.1 and BA.2.86 in the spike protein. JN.1 has inherited more than 30 mutations in its spike protein. It also acquired a new mutation,L455S, which further decreases the ability of antibodies to bind to the virus and prevent infection. A nonspike protein that is heavily mutated in JN.1 is the NSP3 protein. There are six mutations in NSP3 protein, namely T24I, V238L, G489S, K1155R, N1708S, and A1892T. NSP3 is one of the most active proteins in the virus, playing roles in viral RNA binding, polyprotein processing, and other functions. While the exact function of these mutations is unknown, they are likely to increase the efficiency of many of these mechanisms, creating a more functional and pathogenetic virus.The N protein is heavily mutated, R203K and G204R have been mutated in most virus variants throughout the pandemic and likely improve viral replication rate. The other mutations in N may also work to improve viral replication. While the Orf8 protein is truncated in the widespread XBB.1.5 variant, it is fully present in JN.1.
The symptoms of JN.1 appear to be similar to those caused by other strains, which include sore throat, congestion, runny nose, cough, fatigue, headache, muscle aches, fever or chills, loss of sense of taste or smell, shortness of breath or difficulty breathing, nausea or vomiting and diarrhea.
Some doctors have reported that upper respiratory symptoms seem to follow a pattern of starting with a sore throat, followed by congestion and a cough.
Aim: The purpose of the manuscript is to present a systematic review on the prevalence, structural, genomic, and pathogenic characteristics of JN.1 from January 1 to February 29, 2024, emphasizing on the variant genetic characteristics, contagiousness, and potential pathogenicity.
Material and Methods: Original scientific articles published in Medline, Pubmed, Science Direct, Web of Science, Scopus, EBSCO and BioMed Central databases, official health organizations (World Health Organization, U.S. Centers for Disease Control and Prevention, European Centre for Disease Prevention and Control) electronic publications, and specialized media in the subject, were electronically searched to accomplish the aim of the study. Articles published in any language were included from January 2024 to present using a variety of keywords in combination. The studies relevant to our review were analysed and compared.
Results and Discussion: The step-change evolution of BA.2.86, combined with the immune-evading features in JN.1, has given the virus a global growth advantage well beyond the XBB.1-based lineages the world faced in 2023. Evidence suggests the human adaptive immune system could still recognise and respond to BA.286 and JN.1 effectively. Updated monovalent vaccines, tests and treatments remain effective against JN.1. There are two elements to “severity”: first if it is more ‘intrinsically’ severe (worse illness with an infection in the absence of any immunity) and second if the virus has greater transmission, causing greater illness and deaths, simply because it infects more people. The latter is certainly the case with JN.1.
Conclusions: The latest data from US-CDC shows JN.1 as the prevalent SARS-CoV-2 variant in the United States. JN.1 in January 2024, quickly increase its prevalence and surpassed other variants, including HV.1 to become the most prevalent strain in The United States of América. JN.1 has a similar transmission rate, exhibits a greater evasive capacity of immune-generated antibodies than HV.1 family of SARS-CoV-2, produce similar symptoms that of other Omicron variants, are expected not to produce an increase in hospitalizations and mortality rate and the SARS-CoV-2 vaccines recently developed by Pfizer and Moderna, must be effective against this Omicron subvariant. For now, the dominant variant JN.1 does not seem harmful in terms of creating a deadly disease but is still contagious enough to not be ignored.
Oscar Cobar
Pharmacogenomics and Nutrigenomics Research Group, School of Chemical Sciences and Pharmacy, University of San Carlos, Guatemala; School of Chemical Sciences and Pharmacy, University of San Carlos, Guatemala.
Stella Cóbar
School of Chemical Sciences and Pharmacy, University of San Carlos, Guatemala.
Abstract
Background: The proteins codified in the Open Reading Frame 1ab -Orf1ab- region of the SARS-CoV-2 genome are the main responsible of the virus transcription, replication, and translation processes inside the human cell.
Once inside the cell, the viral mRNA encode structural and nonstructural proteins, that direct virus assembly, transcription, replication and host control, and the accessory proteins whose function has not been determined.
The largest gene, Orf1ab, contains overlapping open reading frames that encode polyproteins PP1ab and PP1a.
These polyproteins are cleaved to yield 16 nonstructural proteins, NSP1-16.
Production of the longer (PP1ab) or shorter protein (PP1a) depends on a ribosomal frameshifting event.
The proteins, include the papain-like proteinase (NSP3), 3C-like proteinase (NSP5), RNA-dependent RNA polymerase (NSP12, RdRp), helicase (NSP13, HEL), endoRNAse (NSP15), 2′-O-Ribose-Methyltransferase (NSP16) and other nonstructural proteins.
The SARS-CoV-2 nonstructural proteins are responsible for viral transcription, replication, proteolytic processing, suppression of host immune responses, and suppression of host gene expression.
The purpose of the manuscript is to present a systematic review as of September 30, 2023, on the Orf1ab region mutations of the SARS-CoV-2 genome as of September 30, 2023, with the aim to predict, through the mutations profile on that region, the severity of an infection for a new SARS-CoV-2 variant that could emerge in the near future.
Material and Methods: Original scientific articles published in Medline, Pubmed, Science Direct, Web of Science, Scopus, EBSCO and BioMed Central databases, official health organizations (WHO, CDC, ECDEC, NIH) electronic publications, and specialized media in the subject, were electronically searched to accomplish the aim of the study.
Articles published in any language were included from 2020 to present using a variety of keywords in combination.
The studies relevant to our review were analysed and compared.
Results and discussion: The NIH “National Human Genome Research Institute” define the Open Reading Frames (ORFs) as a portion of a DNA sequence that does not include a stop codon.
The Open Reading Frames encode accessory proteins transcribed from the 3′ one-third of the genome to form a set of subgenomic mRNAs (sg mRNAs).
Following entry on the human cell, the viral particle release the genomic RNA molecule that is translated on two large open reading frames, ORF1a and ORF1b.
The resulting polyproteins pp1a and pp1ab are co-translationally and post-translationally processed into the individual non-structural proteins (NSPs) that form the viral replication and transcription complex (RTC).
Translated structural proteins translocate into endoplasmic reticulum (ER) membranes and transit through the ER-to-Golgi intermediate compartment (ERGIC), where interaction with N-encapsidated, newly produced genomic RNA results in budding into the lumen of secretory vesicular compartments.
Two viral proteases, Plpro -NSP3- and 3Cl-pro -NSP5-, process the polyproteins and generate the nonstructural proteins NSP1-NSP16 that directs the transcription, replication and construction of new virions that are secreted by exocytosis from the infected cell.
The evolution of key proteins in viral transcription and replication is clearly observed by carefully studying the structure, function, and evolution of RdRp, Mpro or 3Clpro, and NSP13 proteins directed by the Orf1a and Orf1ab genome mutations.
Conclusions: ORF1ab is cleaved into 16 non-structural proteins involved in SARS-CoV-2 transcription and genome replication.
P323L, P227L, G671S, V776L and A185S are the first five frequent mutations of RdRp (NSP12), the mutations P227L and G671S might have functional consequences in the viral transcription and replication.
Mutations in residues D499 to L514, K545, R555, T611 to M626, G678 to T710, S759 to D761 are directly implicated with the transcription-replication capability of the virus by RdRp.
In Mpro (NSP5) the mutation of residues H41, P132, C145, S145, L226, T234, R298, S301, F305, and Q306 may increase the efficiency of proteolytic cleavage of proteins such as NEMO, thereby improving the ability of the omicron series of viruses to suppress the immune system and accelerate the viral replication.
In Helicase (NSP13) the mutations of residues E261, K218, K288, S289, H290, D374, E375, Q404, K460, R567, and A598 are involved in the separation of the double-stranded RNA or DNA with a 5′→3′ polarity as well as 5′ mRNA capping activity in the virus transcription-replication process.
In the Orf1ab gene, ORF1b:V2354F mutation, corresponding to NSP15:V303F, may induce a conformational change and result in a disruption to a flanking beta-sheet structure.
The premature stop codon ORF7a:Q94*, truncates the transmembrane protein and cytosolic tail used to mediate protein transport, may affect protein localization to the ER-Golgi.
The analyses of Orf1ab genome mutations, allows us to predict, through the mutations profile on that region, the severity of an infection for a new SARS-CoV-2 variant that could emerge in the near future.
Oscar Cobar
School of Health Sciences, University of Isthmus, Guatemala; Pharmacogenomics and Nutrigenomics Research Group, School of Chemical Sciences and Pharmacy, University of San Carlos, Guatemala.
Stella Cobar
School of Chemical Sciences and Pharmacy, University of San Carlos, Guatemala.
Abstract
Background: The World Health Organization -WHO- declares the end of COVID-19 pandemic on May 5, 2023, and the contagious and pathogenic XBB.2.3 “Acrux” begins to spread worldwide. XBB.2.3 has a higher transmission rate and greater evasive capacity of immune-generated antibodies and vaccines than the XBB.1.16 strain, the potential to evade all forms of immunity, including those conferred by current booster vaccination or by previous infections, besides that current virus vaccines and their boosters may provide little or no protection against XBB.2.3*. Those infected with XBB.2.3*, are expected to acquire more opportunistic secondary infections that contribute to the severity of the disease and more long-term problems (Post-COVID Syndrome) and a possible increase in the mortality rate.
Aim: The purpose of the manuscript is to present a systematic review on the prevalence, structural, genomic, and pathogenic characteristics of XBB.2.3 and its descendants as of May 31, 2023, emphasizing the symptoms generated in children, adults, and the elderly.
Material and methods: Original scientific articles published in Medline, Pubmed, Science Direct, Web of Science, Scopus, EBSCO and BioMed Central databases, official health organizations (WHO, CDC, ECDEC, DOH Philippines) electronic publications, and specialized media in the subject, were electronically searched to accomplish the aim of the study. Articles published in any language were included from 2020 to present using a variety of keywords in combination. The studies relevant to our review were analysed and compared.
Results and discussion: XBB.2.3 probably originated in India, but is expanding, being detected as early as Europe in mid-January 2023 and as of May 31, 2023, in more than 47 countries, including the United States, India, Philippines and Thailand. XBB.2.3* has five defining mutations; S:D253G (previously found in Lambda and Iota variants), S:P521S (new since XBB family), S:S486P and the unprecedented ORF1a:G2091S, and ORF7a:A13V. S:S486P is probably the responsible of the superior transmissibility of XBB.2.3*, appears to have a 37% rate of infection and hospitalisation, which is 3-8% higher than other sub-variants.
Conclusions: XBB.2.3* SARS-CoV-2 strain has a higher transmission rate than XBB.1.16*, exhibits a greater evasive capacity of immune-generated antibodies and vaccines than XBB.1.16*, and even has the potential to evade all forms of immunity, including those conferred by current booster vaccination or by previous infections. Those infected with XBB.2.3*, are expected to acquire more opportunistic secondary infections that contribute to the severity of the disease and more long-term problems (Post-COVID Syndrome) and a possible increase in the mortality rate. Preliminary data from the study suggest that current virus vaccines and their current boosters may provide little or no protection against XBB.2.3*. The potential consequences of XBB.2.3* underscore the importance of coordinated, proactive and productive efforts to contain its spread.
Oscar Cobar
Pharmacogenomics and Nutrigenomics Research Laboratory, School of Chemical Sciences and Pharmacy, University of San Carlos, Guatemala.; Biomedical Sciences, Ph.D. Program, School of Medical Sciences, University of San Carlos, Guatemala.
Stella Cobar
School of Chemical Sciences and Pharmacy, University of San Carlos, Guatemala.
Abstract
Background: One of the major problems in drug design is to enhance the drug’s potency against genetic variants, for which adding a suitable pharmacophore to a newly designed molecule is preferred.
RNA-dependent RNA polymerase (RdRp) is the SARS-CoV-2 enzyme responsible for genome replication and gene transcription into the human cell.
Cryogenic Electron Microscopy resolved the first structure of the RdRp complex of SARS-CoV-2 in April 2020, followed by two other studies that reported similar structures that same year.
The RdRp complex is built up from several nonstructural proteins included nsp12, nsp7, and nsp8.
The protein nsp12 represents the core component and the catalytic subunit of RdRp, while nsp7 and nsp8 are accessory factors that increase the binding and processivity of the RdRp template.
The nsp12 subunit contains an N-terminal nidovirus RdRp-associated nucleotidyltransferase (NiRAN) domain, an interface domain and a C-terminal RdRp domain.
Subunits nsp7 and nsp8 bind to the thumb, and an additional copy of nsp8 binds to the fingers domain.
During replication, the active site of RdRp is responsible for incorporating free nucleotides into the daughter RNA strand of the replication complex.
RdRp inhibitors, once metabolized, compete with the viral ATP molecules for incorporation into the nascent RNA strand.
Once the RdRp drug replaces ATP in the new strand, the RNA synthesis process is terminated, thereby preventing further replication of the virus from occurring.
In several studies reviewed in this manuscript, Molecular Docking simulations was employed to screen inhibitors that showed binding interaction with the conserved residues of RdRp.
Aim: The purpose of the Review is to present a literature review from January 1, 2023, to April 30, 2024, on the advances in SARS-CoV-2 RdRp inhibitors as a therapeutic approach against the virus, emphasizing on the structure of the enzime, the non-structural proteins that comprises, in particular nsp12, nsp 8 and nsp 7, the mechanisms that underlie the antiviral activity of RdRp inhibitory substances, the structure of the nucleoside analogs that have demonstrated RdRp inhibition in structural biology and computational research studies, and examine the current understanding of the molecular mechanisms underlying the action of these nucleoside analogs.
Materials and Methods: Original scientific articles published in Medline, Pubmed, Science Direct, Web of Science, Scopus, EBSCO and BioMed Central databases, official health organizations (World Health Organization, U.S. Centers for Disease Control and Prevention, European Centre for Disease Prevention and Control) electronic publications, and specialized media in the subject, were electronically searched to accomplish the aim of the study. Articles published in any language were included from January 1, 2023, to April 30, 2024, using a variety of keywords in combination. The studies relevant to our review were analyzed and compared.
Results and Discussion:
Inhibition of RdRp´s has been an integral approach for managing various viral infections such as dengue, influenza, Hepatitis C (HCV), Bovine Viral Diarrhea Virus (BVDV), among others. Inhibition of the SARS-CoV-2 RdRp is currently rigorously explored for the treatment of COVID-19. Consequently, the importance of RdRp in developing anti-viral agents against this viral disease, has been discussed by the scientific community in the last four years. The structure activity relationship profile and binding conformations of the reported inhibitors are essential features to elucidate some hypothesis for the designing of further SARS-CoV-2 RdRp inhibitors.
The search on scientific literature on these inhibitors, the analyses of the interaction characteristics, together with the examination of the inhibitors chemical structure, it would guide the rational design of antiviral medications and research into viral transcriptional mechanisms.
Conclusions: Several RdRp inhibitors have shown promising results for their use in treating the SARS-CoV-2 virus.
While work must still be conducted to fully understand the mechanisms responsible for reducing the antiviral activity of SARS-CoV-2, their potential in healing infected individuals is extremely valuable.
The development of SARS-CoV-2 RdRp inhibitors, to relieve the severity of an infection for a SARS-CoV-2 variants that could emerge in the near future, it is an essential task for the scientific community.
The analyses of inhibitors chemical structure-RdRp, besides the analyses of the inhibitors-RdRp interactions, it would guide the rational design of antiviral medications and research into SARS-CoV-2 transcriptional mechanisms.
This review summarizes recent progress in studies of RdRp inhibitors, 87 compounds was tested, focusing on the chemical structure of the inhibitors and the interactions between these inhibitors and the enzyme complex.
