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De novo design of picomolar SARS-CoV-2 miniprotein inhibitors

Longxing Cao, Inna Goreshnik, Brian Coventry, James Brett Case, Lauren Miller, Lisa Kozodoy,Rita E. Chen, Lauren Carter, Alexandra C. Walls, Young-Jun Park, Eva-Maria Strauch, Lance Stewart, Michael S. Diamond, David Veesler, David Baker, Science  09 Sep 2020:
DOI: 10.1126/science.abd9909



Targeting the interaction between the SARS-CoV-2 Spike protein and the human ACE2 receptor is a promising therapeutic strategy. We designed inhibitors using two de novo design approaches. Computer generated scaffolds were either built around an ACE2 helix that interacts with the Spike receptor binding domain (RBD), or docked against the RBD to identify new binding modes, and their amino acid sequences designed to optimize target binding, folding and stability. Ten designs bound the RBD with affinities ranging from 100pM to 10nM, and blocked ARS-CoV-2 infection of Vero E6 cells with IC 50 values between 24 pM and 35 nM; The most potent, with new binding modes, are 56 and 64 residue proteins (IC 50 ~ 0.16 ng/ml). Cryo-electron microscopy structures of these minibinders in complex with the SARS-CoV-2 spike ectodomain trimer with all three RBDs bound are nearly identical to the computational models. These hyperstable minibinders provide starting points for SARS-CoV-2 therapeutics.


Molecular interaction and inhibition of SARS-CoV-2 binding to the ACE2 receptor

Jinsung Yang, Simon J. L. Petitjean, Melanie Koehler, Qingrong Zhang, Andra C. Dumitru, Wenzhang Chen, Sylvie Derclaye, Stéphane P. Vincent, Patrice Soumillion, David Alsteens, Nat Commun, 2020, 11, 4541.

DOI: https://doi.org/10.1038/s41467-020-18319-6


Study of the interactions established between the viral glycoproteins and their host receptors is of critical importance for a better understanding of virus entry into cells. The novel coronavirus SARS-CoV-2 entry into host cells is mediated by its spike glycoprotein (S-glycoprotein), and the angiotensin-converting enzyme 2 (ACE2) has been identified as a cellular receptor. Here, we use atomic force microscopy to investigate the mechanisms by which the S-glycoprotein binds to the ACE2 receptor. We demonstrate, both on model surfaces and on living cells, that the receptor binding domain (RBD) serves as the binding interface within the S-glycoprotein with the ACE2 receptor and extract the kinetic and thermodynamic properties of this binding pocket. Altogether, these results provide a picture of the established interaction on living cells. Finally, we test several binding inhibitor peptides targeting the virus early attachment stages, offering new perspectives in the treatment of the SARS-CoV-2 infection.


Immuno-Informatics Quest against COVID-19/SARS-COV-2: Determining Putative T-Cell Epitopes for Vaccine Prediction


Nahid Akhtar,  Amit Joshi, Bhupender Singh, Vikas Kaushik, Infect Disord Drug Targets2020 Sep 21.

DOI: 10.2174/1871526520666200921154149


Background: Since, December 2019 a novel coronavirus, SARS-CoV-2 has caused global public health issue after being reported for the first time in Wuhan province of China. So far, there have been approximately 14.8 million confirmed cases and 0.614 million deaths due to the SARS-CoV-2 infection globally, and still numbers are increasing. Although, the virus has caused a global public health concern, no effective treatment has been developed.

Objective: One of the strategies to combat the COVID-19 disease caused by SARS-CoV-2 is development of vaccines that can make humans immune to these infections. Considering this approach, in this study an attempt has been made to design epitope based vaccine for combatting COVID-19 disease by analyzing the complete proteome of the virus by using immuno-informatics tools.

Methods: The protein sequence of the SARS-CoV-2 was retrieved and the individual proteins were checked for their allergic potential. Then, from non-allergen proteins antigenic epitopes were identified that could bind with MHCII molecules. The epitopes were modeled and docked to predict the interaction with MHCII molecules. The stability of the epitopeMHCII complex was further analyzed by performing molecular dynamic simulation study. The selected vaccine candidates were also analyzed for their global population coverage and conservancy among SARS related coronavirus species.

Results: The study has predicted 5 peptide molecules that can act as potential candidate for epitope based vaccine development. Among the 5 selected epitopes, the peptide LRARSVSPK can be the most potent epitope because of its high geometric shape complementarity score, low ACE and very high response to it by the world population (81.81% global population coverage). Further, molecular dynamic simulation analysis indicated the formation of stable epitope-MHCII complex. The epitope LRARSVSPK was also found to be highly conserved among the SARS-CoV-2 isolated from different countries.

Conclusion: The study has predicted T-cell epitopes that can elicit robust immune response in global human population and act as potential vaccine candidates. However, the ability of these epitopes to act as vaccine candidate needs to be validated in wet lab studies.

Heparin-binding peptides as novel therapies to stop SARS-CoV-2 cellular entry and infection

Omid Tavassoly, Farinaz Safavi, Iman Tavassoly, Mol Pharmacol2020 Sep 10;MOLPHARM-MR-2020-000098.

doi: 10.1124/molpharm.120.000098.Online ahead of print.

Heparan Sulfate Proteoglycans (HSPGs) are cell surface receptors that are involved in the cellular uptake of pathological amyloid proteins and viruses, including the novel coronavirus; Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV-2). Heparin and heparan sulfate antagonize the binding of these pathogens to HSPGs and stop their cellular internalization, but the anticoagulant effect of these agents has been limiting their use in the treatment of viral infections. Heparin-binding peptides (HBPs) are suitable non-anticoagulant agents that are capable to antagonize binding of heparin-binding pathogens to HSPGs. Here, we review and discuss the use of HBPs as viral uptake inhibitors and will address their benefits and limitations to treat viral infections. Furthermore, we will discuss a variant of these peptides that is in the clinic and can be considered as a novel therapy in Corona Virus Disease-2019 (COVID-19) infection. Significance Statement The need to discover treatment modalities for COVID-19 is a necessity, and therapeutic interventions such as Heparin-binding Peptides (HBPs), which are used for other cases, can be beneficial based on their mechanisms of actions. In this paper, we have discussed the application of HBPs as viral uptake inhibitors in COVID-19 and explained possible mechanisms of actions and the therapeutic effects.

Functional mapping of B-cell linear epitopes of SARS-CoV-2 in COVID-19 convalescent population

Zhigang Yi, Yun Ling, Xiaonan Zhang, Jieliang Chen, Kongying Hu, Yuyan Wang, Wuhui Song, Tianlei Ying, Rong Zhang, HongZhou Lu, Zhenghong Yuan, Emerg. Microbes Infect.,2020, 9, 1988-1996.

Doi: 10.1080/22221751.2020.1815591


Pandemic SARS-CoV-2 has caused unprecedented mortalities. Vaccine is in urgent need to stop the pandemic. Despite great progresses on SARS-CoV-2 vaccine development, the efficacy of the vaccines remains to be determined. Deciphering the interactions of the viral epitopes with the elicited neutralizing antibodies in convalescent population inspires the vaccine development. In this study, we devised a peptide array composed of 20-mer overlapped peptides of spike (S), membrane (M) and envelope (E) proteins, and performed a screening with 120 COVID-19 convalescent sera and 24 non-COVID-19 sera. We identified five SARS-CoV-2-specific dominant epitopes that reacted with above 40% COVID-19 convalescent sera. Of note, two peptides non-specifically interacted with most of the non-COVID-19 sera. Neutralization assay indicated that only five sera completely blocked viral infection at the dilution of 1:200. By using a peptide-compete neutralizing assay, we found that three dominant epitopes partially competed the neutralization activity of several convalescent sera, suggesting antibodies elicited by these epitopes played an important role in neutralizing viral infection. The epitopes we identified in this study may serve as vaccine candidates to elicit neutralizing antibodies in most vaccinated people or specific antigens for SARS-CoV-2 diagnosis.

Highly conserved binding region of ACE2 as a receptor for SARS-CoV-2 between humans and mammals

Takuma Hayashi, Kaoru Abiko, Masaki Mandai, Nobuo Yaegashi, Ikuo Konishi, Vet Q., 2020, Sep 12;1-8.

doi: 10.1080/01652176.2020.1823522.  Online ahead of print.


Background: Several cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection transmitted from human owners to their dogs have recently been reported. The first ever case of SARS-CoV-2 transmission from a human owner to a domestic cat was confirmed on March 27, 2020. A tiger from a zoo in New York, USA, was also reportedly infected with SARS-CoV-2. It is believed that SARS-CoV-2 was transmitted to tigers from their caretakers, who were previously infected with this virus. On May 25, 2020, the Dutch Minister of Agriculture, Nature and Food Quality reported that two employees were infected with SARS-CoV-2 transmitted from minks. Objective: These reports have influenced us to perform a comparative analysis among angiotensin-converting enzyme 2 (ACE2) homologous proteins for verifying the conservation of specific protein regions. One of the most conserved peptides is represented by the peptide “353-KGDFR-357 (H. sapiens ACE2 residue numbering), which is located on the surface of the ACE2 molecule and participates in the binding of SARS-CoV-2 spike receptor binding domain (RBD). Methods: Multiple sequence alignments of the ACE2 proteins by ClustalW, whereas the three-dimensional structure of its binding region for the spike glycoprotein of SARS-CoV-2 was assessed by means of Spanner, a structural homology modeling pipeline method. In addition, evolutionary phylogenetic tree analysis by ETE3 was used. Results: ACE2 works as a receptor for the SARS-CoV-2 spike glycoprotein between humans, dogs, cats, tigers, minks, and other animals, except for snakes. The three-dimensional structure of the KGDFR hosting protein region involved in direct interactions with SARS-CoV-2 spike RBD of the mink ACE2 appears to form a loop structurally related to the human ACE2 corresponding protein loop, despite of the reduced available protein length (401 residues of the mink ACE2 available sequence vs 805 residues of the human ACE2). The multiple sequence alignments of the ACE2 proteins shows high homology and complete conservation of the five amino acid residues: 353-KGDFR-357 with humans, dogs, cats, tigers, minks, and other animals, except for snakes. Conclusion: Where the information revealed from our examinations can support precision vaccine design and the discovery of antiviral therapeutics, which will accelerate the development of medical countermeasures, the World Health Organization recently reported on the possible risks of reciprocal infections regarding SARS-CoV-2 transmission from animals to humans.

Fusion protein targeted antiviral peptides: fragment based drug design (FBDD) guided rational design of dipeptides against SARS-CoV-2

Sounik Manna, Trinath Chowdhury, Piyush Baindara, Santi M Mandal, Curr Protein Pept Sci. 2020 Sep 8.

doi: 10.2174/1389203721666200908164641.Online ahead of print.


Infectious diseases caused by viruses become a serious public health issue in the recent past, including current pandemic situation of COVID-19. Enveloped viruses are most commonly known to cause emerging and recurring infectious diseases. Viral and cell membrane fusion is the major key event in case of enveloped viruses that required for their entry into the cell. Viral fusion proteins are playing important role in fusion process and in infection establishment. Because of this, fusion process targeting antivirals become an interest to fight against viral diseases caused by enveloped virus. Lower respiratory tract infections casing viruses like influenza, respiratory syncytial virus (RSV) and severe acute respiratory syndrome corona virus (SARS-CoV) are examples of such enveloped viruses that are at top in public health issues. Here, we summarized the viral fusion protein targeted antiviral peptides along with their mechanism and specific design to combat viral fusion process. The pandemic COVID-19, severe respiratory syndrome disease is outbreak worldwide. There are no definitive drugs yet but few are in on-going trial. Here, an approach of fragment based drug design (FBDD) methodology was used to identify the broad spectrum agent target to the conserved region of fusion protein of SARS CoV-2. Three dipeptides (DL, LQ and ID) were chosen from the library and designed by the systematic combination along with their possible modifications of amino acids to the target sites. Designed peptides were docked with targeted fusion protein after energy minimization. Results show strong and significant binding affinity (DL = -60.1 kcal/mol; LQ = -62.8 kcal/mol; ID= -71.5 kcal/mol) during interaction. Any one of the active peptides from the developed libraries may help to block competitively the target sites to successfully control COVID-19.

Oxytocin as a Potential Adjuvant against COVID-19 Infection

Pratibha Thakur, Renu Shrivastava, Vinoy Kumar Shrivastava, Endocr Metab Immune Disord Drug Targets2020 Sep 10.

doi: 10.2174/1871530320666200910114259. Online ahead of print.


This article summarizes the benefits of Oxytocin (OT) in the attenuation of coronavirus infectious disease (COVID-19) pathogenesis. The recent outbreak of COVID-19 has become pandemic with 7,323,761 of infected patients and has created health emergency throughout the world. On the basis of clinical study, COVID-19 shows homology with other coronavirus pathogenesis i.e. inflammation, oxidative stress, and hyper-activation of immune system, results cytokine storm and causes acute lung infection (ALI), acute respiratory distress syndrome (ARDS), and kidney dysfunction. OT is a peptide of nine amino acid, well known anti-inflammatory, anti-oxidant, and immune-modulator molecule protective against ALI/ARDS, nephrotoxicity, sepsis, and ischemia-reperfusion medical condition. OT is a neuromodulatory, effective for stress, anxiety, social behaviour, and depression, which might be helpful for better output of COVID-19 patients. There is significant data showing OT would be useful for treatment of COVID-19 pathogenesis. Direct application of OT in COVID19 is unclear, but its use in experimental model as well as human has continuously documented its safety, and its use by COVID-19 patients predictably would be highly beneficial.