March 13, 2020

In Silico Fight Against Novel Coronavirus by Finding Chromone Derivatives as Inhibitor of Coronavirus Main Proteases Enzyme

Benzylidenechromanones, naturally occurring oxygen heterocyclic compounds, having capability to inhibit various protein and receptors, have been designed here to block mutant variety of coronavirus main protease enzyme (CoV Mpro ) isolated from 2019-nCoV with the assistance of molecular docking, bioinformatics and DFT. ( Z )-3-(4’-chlorobenzylidene)-thiochroman-4-one showed highest binding affinity to the protein. Binding of a compound to this protein actually inhibit the replication and transcription of the virus and ultimately, stop the virus multiplication. Incorporation of any functional groups to the basic benzylidenechromanones enhance their binding ability. Chloro and bromo substitution amplify the binding affinity. ADME studies of all these compounds indicates they are lipophilic, high gastro intestine absorbable and blood-brain barrier permeable. The outcome reveal that the investigated benzylidenechromanones can be examine in the case of 2019-nCoV as potent inhibitory drug of CoV M pro , for their strong inhibition ability, high reactivity, and effective pharmacological properties.

March 11, 2020

SARS-CoV-2 Infected Host Cell Proteomics Reveal Potential Therapy Targets

Here we identify the host cell pathways modulated by SARS-CoV-19 infection and reveal that drugs targeting pathways prevent viral replication in human cells. We established a human cell culture model for infection with SARS-CoV-2 clinical isolate. Employing this system, we determined the SARS-CoV-2 infection profile by translatome and proteome proteomics at different times after infection. These analyses revealed that SARS-CoV-2 reshapes central cellular pathways, such as translation, splicing, carbon metabolism and nucleic acid metabolism. Small molecule inhibitors targeting these pathways were tested in cellular infection assays and prevented viral replication. Our results reveal the cellular infection profile of SARS-CoV-2 and led to the identification of drugs inhibiting viral replication.

March 9, 2020

Research and Development on Therapeutic Agents and Vaccines for COVID-19 and Related Human Coronavirus Diseases

To support the current research and development, CAS has produced a special report to provide an overview of published scientific information with an emphasis on patents in the CAS content collection. It highlights antiviral strategies involving small molecules and biologics targeting complex molecular interactions involved in coronavirus infection and replication. The drug-repurposing effort documented herein focuses primarily on agents known to be effective against other RNA viruses including SARS-CoV and MERS-CoV. The patent analysis of coronavirus related biologics includes therapeutic antibodies, cytokines, and nucleic acid-based therapies targeting virus gene expression as well as various types of vaccines. More than 500 patents disclose methodologies of these four biologics with the potential for treating and preventing coronavirus infections, which may be applicable to COVID-19. The information included in this report provides a strong intellectual groundwork for the ongoing development of therapeutic agents and vaccines.

March 8, 2020

Bioinformatic Analysis of Epitope-Based Vaccine Design Against the Novel SARS-COV-2

A total of 63 sequential B-cell epitopes on spike protein were predicted and 3 peptides (333-338, 648-663, 1064-1079) exhibited high antigenicity score and good surface accessibility in our modeling. 8 residues within spike protein (Gly184, Gly502, Lys558, Pro561, Pro809, Ser810, Lys811, Pro812) are forcasted as components of discontinuous B-cell epitopes. The bioinformatic analysis of HLA binding peptides within nucleocapsid protein produced 81 and 64 peptides being able to bind class-I and class-II molecule respectively. The peptide (104-112) has a high immunogenicity score and was predicted to bind a wide spectrum of both HLA-1 and HLA-2 molecules. Linear B-cell epitopes (333-338, 648-663, 1064-1079) and discontinuous Bcell epitopes (Gly184, Gly502, Lys558, Pro561, Pro809, Ser810, Lys811, Pro812) on spike protein, T-cell epitope (104-112) within nucleocapsid protein were identified and recommended for developing vaccine against SARS-COV-2.

March 6, 2020

A Sequence Homology and Bioinformatic Approach Can Predict Candidate Targets for Immune Responses to SARS-CoV-2

Effective countermeasures against the recent emergence and rapid expansion of the 2019-Novel Coronavirus (SARS-CoV-2) require the development of data and tools to understand and monitor its spread and immune responses to it. However, little information is available about the targets of immune responses to SARS-CoV-2. We used the Immune Epitope Database and Analysis Resource (IEDB) to catalog available data related to other coronaviruses. This includes SARS-CoV, which has high sequence similarity to SARS-CoV-2 and is the best-characterized coronavirus in terms of epitope responses. We identified multiple specific regions in SARS-CoV-2 that have high homology to the SARS-CoV virus. Parallel bioinformatic predictions identified a priori potential B and T cell epitopes for SARS-CoV-2. The independent identification of the same regions using two approaches reflects the high probability that these regions are promising targets for immune recognition of SARS-CoV-2. These predictions can facilitate effective vaccine design against this virus of high priority.

March 3, 2020

Rapid Development of a Synthetic DNA Vaccine for COVID-19

As of February 25, 2020 there are 80,994 people infected and 2,760 deaths, and documented human-to-human transmission across multiple continents. At this time, no vaccine is available to control further dissemination of the disease. We have previously developed a synthetic DNA vaccine targeting the MERS coronavirus Spike (S) protein that was deployed in response to the MERS outbreak in South Korea. This vaccine induced potent antibody and CTL responses, and provided

protection in a NHP challenge model. In the clinic, the vaccine generated humoral immunity including neutralizing antibody responses, as well as T cell immunity. Here we build on this prior work and report on the rapid development of a synthetic DNA-based vaccine targeting the major surface antigen Spike protein of SARS-CoV-2. The engineered construct, INO-4800 induced robust expression of the Spike protein in vitro, and generated antibody and T cell responses following a single immunization in mice and guinea pigs. This preliminary dataset identifies INO-4800 as a potential COVID-19 vaccine candidate, supporting further study for mobilization against this emerging disease threat.

February 25, 2020

Preliminary Identification of Potential Vaccine Targets for the COVID-19 Coronavirus (SARS-CoV-2) Based on SARS-CoV Immunological Studies

The beginning of 2020 has seen the emergence of COVID-19 outbreak caused by a novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). There is an imminent need to better understand this new virus and to develop ways to control its spread. In this study, we sought to gain insights for vaccine design against SARS-CoV-2 by considering the high genetic similarity between SARS-CoV-2 and SARS-CoV, which caused the outbreak in 2003, and leveraging existing immunological studies of SARS-CoV. By screening the experimentally determined SARS-CoV-derived B cell and T cell epitopes in the immunogenic structural proteins of SARS-CoV, we identified a set of B cell and T cell epitopes derived from the spike (S) and nucleocapsid (N) proteins that map identically to SARS-CoV-2 proteins. As no mutation has been observed in these identified epitopes among the 120 available SARS-CoV-2 sequences (as of 21 February 2020), immune targeting of these epitopes may potentially offer protection against this novel virus. For the T cell epitopes, we performed a population coverage analysis of the associated MHC alleles and proposed a set of epitopes that is estimated to provide broad coverage globally, as well as in China. Our findings provide a screened set of epitopes that can help guide experimental efforts towards the development of vaccines against SARS-CoV-2.

February 21, 2020

Structural Modeling and Conserved Epitopes Prediction Against SARS-COV-2 Structural Proteins for Vaccine Development

The antigenic B-cell epitopes exposed to the outer surface were screened out and 23 linear B cell epitopes were selected. “SPTKLNDLCFTNVY” had the highest antigenicity score among B cell epitopes. The T-cell epitopes bound to multiple alleles, antigenic, non-allergen, non-toxic, and conserved in the protein sequence were

shortlisted. In total, 16 epitopes (9 from MHC class I and 7 from MHC class II) were selected. Among the T-cell epitopes, MHC class I (IPFAMQMAYRFN) and MHC class II (VTLACFVLAAVYRIN) were classified as strongly antigenic. Digestion analysis verified the safety and stability of the peptides predicted during this study. Furthermore, docking analyses of predicted peptides showed significant interactions with the HLA-B7 allele.