In silico Antibody Mutagenesis for Optimizing its Binding to the Spike Protein of SARS-CoV-2

10.26434/chemrxiv.12967832.v1 ◽

2020 ◽

Author(s):

Binquan Luan ◽

Tien Huynh

Keyword(s):

Clinical Trials ◽

Monoclonal Antibodies ◽

Drug Discovery ◽

In Silico ◽

Spike Protein ◽

Computing Power ◽

Atomic Structures ◽

Protein Mutagenesis ◽

Small Molecule Drugs ◽

Global Pandemic

Coronavirus disease 2019 (COVID-19) is an ongoing global pandemic and there are currently no FDA approved medicines for treatment or prevention. Inspired by promising outcomes for convalescent plasma treatment, developing antibody drugs (biologics) to block SARS-CoV-2 infection has been the focus of drug discovery, along with tremendous efforts in repurposing small-molecule drugs. In the last several months, experimentally, many human neutralizing monoclonal antibodies (mAbs) were successfully extracted from plasma of recovered COVID-19 patients. Currently, several mAbs targeting the SARS-CoV-2's spike protein (Spro) are in clinical trials. With known atomic structures of mAb-Spro complex, it becomes possible to in silico investigate the molecular mechanism of mAb's binding with Spro and design more potent mAbs through protein mutagenesis studies, complementary to existing experimental efforts. Leveraging superb computing power nowadays, we propose a fully automated in silico protocol for quickly identifying possible mutations in a mAb (e.g.~CB6) to enhance its binding affinity with Spro for the design of more efficacious therapeutic mAbs.

Download Full-text

Sitagliptin: a potential drug for the treatment of SARS-CoV-2?

10.31222/osf.io/78mbt ◽

2020 ◽

Author(s):

Sanaa Bardaweel

Keyword(s):

Clinical Trials ◽

Drug Discovery ◽

Antimalarial Drug ◽

Drug Repurposing ◽

Spike Protein ◽

Diabetic Patients ◽

Potential Drug ◽

Chemokine Production ◽

Drug Discovery And Development ◽

Sequence Identity

Recently, an outbreak of fatal coronavirus, SARS-CoV-2, has emerged from China and is rapidly spreading worldwide. As the coronavirus pandemic rages, drug discovery and development become even more challenging. Drug repurposing of the antimalarial drug chloroquine and its hydroxylated form had demonstrated apparent effectiveness in the treatment of COVID-19 associated pneumonia in clinical trials. SARS-CoV-2 spike protein shares 31.9% sequence identity with the spike protein presents in the Middle East Respiratory Syndrome Corona Virus (MERS-CoV), which infects cells through the interaction of its spike protein with the DPP4 receptor found on macrophages. Sitagliptin, a DPP4 inhibitor, that is known for its antidiabetic, immunoregulatory, anti-inflammatory, and beneficial cardiometabolic effects has been shown to reverse macrophage responses in MERS-CoV infection and reduce CXCL10 chemokine production in AIDS patients. We suggest that Sitagliptin may be beneficial alternative for the treatment of COVID-19 disease especially in diabetic patients and patients with preexisting cardiovascular conditions who are already at higher risk of COVID-19 infection.

Download Full-text

SARS-CoV-2 variants resist antibody neutralization and broaden host ACE2 usage

10.1101/2021.03.09.434497 ◽

2021 ◽

Author(s):

Ruoke Wang ◽

Qi Zhang ◽

Jiwan Ge ◽

Wenlin Ren ◽

Rui Zhang ◽

...

Keyword(s):

South Africa ◽

Monoclonal Antibodies ◽

Molecular Basis ◽

Spike Protein ◽

Receptor Binding Domain ◽

Antibody Neutralization ◽

Vaccine Protection ◽

Antigenic Sites ◽

Global Pandemic ◽

Crystal Structural

AbstractNew SARS-CoV-2 variants continue to emerge from the current global pandemic, some of which can replicate faster and with greater transmissibility and pathogenicity. In particular, UK501Y.V1 identified in UK, SA501Y.V2 in South Africa, and BR501Y.V3 in Brazil are raising serious concerns as they spread quickly and contain spike protein mutations that may facilitate escape from current antibody therapies and vaccine protection. Here, we constructed a panel of 28 SARS-CoV-2 pseudoviruses bearing single or combined mutations found in the spike protein of these three variants, as well as additional nine mutations that within or close by the major antigenic sites in the spike protein identified in the GISAID database. These pseudoviruses were tested against a panel of monoclonal antibodies (mAbs), including some approved for emergency use to treat SARS-CoV-2 infection, and convalescent patient plasma collected early in the pandemic. SA501Y.V2 pseudovirus was the most resistant, in magnitude and breadth, against mAbs and convalescent plasma, followed by BR501Y.V3, and then UK501Y.V1. This resistance hierarchy corresponds with Y144del and 242-244del mutations in the N-terminal domain as well as K417N/T, E484K and N501Y mutations in the receptor binding domain (RBD). Crystal structural analysis of RBD carrying triple K417N-E484K-N501Y mutations found in SA501Y.V2 bound with mAb P2C-1F11 revealed a molecular basis for antibody neutralization and escape. SA501Y.V2 and BR501Y.V3 also acquired substantial ability to use mouse and mink ACE2 for entry. Taken together, our results clearly demonstrate major antigenic shifts and potentially broadening the host range of SA501Y.V2 and BR501Y.V3, which pose serious challenges to our current antibody therapies and vaccine protection.

Download Full-text

Molecular rationale for SARS-CoV-2 spike circulating mutations able to escape bamlanivimab and etesevimab monoclonal antibodies

Scientific Reports ◽

10.1038/s41598-021-99827-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Erik Laurini ◽

Domenico Marson ◽

Suzana Aulic ◽

Alice Fermeglia ◽

Sabrina Pricl

Keyword(s):

Monoclonal Antibodies ◽

In Silico ◽

Structural Information ◽

Viral Evolution ◽

Protein A ◽

Immune Surveillance ◽

Protein S ◽

Spike Protein ◽

Wild Type ◽

Experimental Findings

AbstractThe purpose of this work is to provide an in silico molecular rationale of the role eventually played by currently circulating mutations in the receptor binding domain of the SARS-CoV-2 spike protein (S-RBDCoV‑2) in evading the immune surveillance effects elicited by the two Eli Lilly LY-CoV555/bamlanivimab and LY-CoV016/etesevimab monoclonal antibodies. The main findings from this study show that, compared to the wild-type SARS-CoV-2 spike protein, mutations E484A/G/K/Q/R/V, Q493K/L/R, S494A/P/R, L452R and F490S are predicted to be markedly resistant to neutralization by LY-CoV555, while mutations K417E/N/T, D420A/G/N, N460I/K/S/T, T415P, and Y489C/S are predicted to confer LY-CoV016 escaping advantage to the viral protein. A challenge of our global in silico results against relevant experimental data resulted in an overall 90% agreement. Thus, the results presented provide a molecular-based rationale for all relative experimental findings, constitute a fast and reliable tool for identifying and prioritizing all present and newly reported circulating spike SARS-CoV-2 variants with respect to antibody neutralization, and yield substantial structural information for the development of next-generation vaccines and monoclonal antibodies more resilient to viral evolution.

Download Full-text

Progress in targeting RAS with small molecule drugs

Biochemical Journal ◽

10.1042/bcj20170441 ◽

2019 ◽

Vol 476 (2) ◽

pp. 365-374 ◽

Cited By ~ 25

Author(s):

Frank McCormick

Keyword(s):

Clinical Trials ◽

Drug Discovery ◽

Small Molecules ◽

Active Site ◽

Biochemical Properties ◽

Ras Proteins ◽

Oncogenic Ras ◽

Small Molecule Drugs ◽

Related Proteins ◽

Effector Binding

Abstract RAS proteins have traditionally been deemed undruggable, as they do not possess an active site to which small molecules could bind but small molecules that target one form of oncogenic RAS, KRAS G12C, are already in preclinical and clinical trials, and several other compounds that bind to different RAS proteins at distinct sites are in earlier stage evaluation. KRAS is the major clinical target, as it is by far the most significant form of RAS in terms of cancer incidence. Unfortunately, KRAS exists in two isoforms, each with unique biochemical properties. This complicates efforts to target KRAS specifically. KRAS is also a member of a family of closely related proteins, which share similar effector-binding regions and G-domains, further increasing the challenge of specificity. Nevertheless, progress is being made, driven by new drug discovery technologies and creative science.

Download Full-text

In-silico Studies of Antimalarial-agent Artemisinin and Derivatives Portray More Potent Binding to Lys353 and Lys31-Binding Hotspots of SARS-CoV-2 Spike Protein than Hydroxychloroquine: Potential Repurposing of Artenimol for COVID-19.

10.26434/chemrxiv.12098652.v1 ◽

2020 ◽

Author(s):

Moussa SEHAILIA ◽

Smain chemat

Keyword(s):

Clinical Trials ◽

In Silico ◽

Spike Protein ◽

Antimalarial Agent ◽

In Silico Studies ◽

Better Than

The role of hydroxychloroquine to prevent hACE2 from interacting with SARS-CoV-2 Spike protein is unveiled. Artemisinin & derived compounds entangle better than hydroxychloroquine into Lys353 and Lys31 binding hotspots of the virus Spike protein, therefore preventing infection occurs. Since these molecules are effective antivirals with excellent safety track records, their potential repurposing is recommended for clinical trials of COVID-19 patients.

Download Full-text

In vitro and in vivo preclinical studies predict REGEN-COV protection against emergence of viral escape in humans

10.1101/2021.03.10.434834 ◽

2021 ◽

Author(s):

Richard Copin ◽

Alina Baum ◽

Elzbieta Wloga ◽

Kristen E. Pascal ◽

Stephanie Giordano ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Therapeutic Option ◽

Viral Escape ◽

Spike Protein ◽

In Vivo Studies ◽

Preclinical Studies ◽

Global Pandemic ◽

Emerging Virus

SummaryMonoclonal antibodies against SARS-CoV-2 are a clinically validated therapeutic option against COVID-19. As rapidly emerging virus mutants are becoming the next major concern in the fight against the global pandemic, it is imperative that these therapeutic treatments provide coverage against circulating variants and do not contribute to development of treatment emergent resistance. To this end, we investigated the sequence diversity of the spike protein and monitored emergence of minor virus variants in SARS-COV-2 isolates found in nature or identified from preclinical in vitro and in vivo studies and in the clinic. This study demonstrates that a combination of noncompeting antibodies not only provides full coverage against currently circulating variants but also protects against emergence of new such variants and their potential seeding into the population in a clinical setting.

Download Full-text

A Minireview of the Promising Drugs and Vaccines in Pipeline for the Treatment of COVID-19 and Current Update on Clinical Trials

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.637378 ◽

2021 ◽

Vol 8 ◽

Author(s):

Jeyanthi Venkadapathi ◽

Venkat Kumar Govindarajan ◽

Saravanan Sekaran ◽

Santhi Venkatapathy

Keyword(s):

Clinical Trials ◽

Monoclonal Antibodies ◽

Viral Vectors ◽

Antiviral Agents ◽

Spike Protein ◽

World Health ◽

The World ◽

The Republic ◽

Health Organization ◽

Day By Day

The COVID-19 is affecting thousands of peoples day by day and continues to spread across the world. The present review has focused on promising repurposing drugs, including remdesivir, lopinvar/retinovar, favipiravir, hydroxychloroquine, monoclonal antibodies and vaccines against the SARS-CoV-2 infection. Besides, our review has also focused on many organizations that are in the race to develop vaccines using various approaches including DNA, RNA, viral vectors and subunit proteins against this highly contagious respiratory disease. The spike protein is being studied by scientists all over the world to develop potential vaccines. The antiviral drugs, antibodies and vaccines developed by various researchers around the world have entered clinical trials in humans. The current clinical trials for antiviral agents and vaccines with promising outcomes are being discussed. So far, four vaccines developed by the Pfizer-BioNTech vaccine, the Johnson and Johnson vaccine and two AstraZeneca vaccines (produced by SKBio in the Republic of Korea and Serum Institute of India) are approved by the World Health Organization for public use.

Download Full-text

In-silico Studies of Antimalarial-agent Artemisinin and Derivatives Portray More Potent Binding to Lys353 and Lys31-Binding Hotspots of SARS-CoV-2 Spike Protein than Hydroxychloroquine: Potential Repurposing of Artenimol for COVID-19.

10.26434/chemrxiv.12098652 ◽

2020 ◽

Author(s):

Moussa SEHAILIA ◽

Smain chemat

Keyword(s):

Clinical Trials ◽

In Silico ◽

Spike Protein ◽

Antimalarial Agent ◽

In Silico Studies ◽

Better Than

The role of hydroxychloroquine to prevent hACE2 from interacting with SARS-CoV-2 Spike protein is unveiled. Artemisinin & derived compounds entangle better than hydroxychloroquine into Lys353 and Lys31 binding hotspots of the virus Spike protein, therefore preventing infection occurs. Since these molecules are effective antivirals with excellent safety track records, their potential repurposing is recommended for clinical trials of COVID-19 patients.

Download Full-text

Structure-based assortment of herbal analogues against spike protein to restrict COVID-19 entry through hACE2 receptor: An in-silico approach

Acta Biologica Szegediensis ◽

10.14232/abs.2020.2.159-171 ◽

2021 ◽

Vol 64 (2) ◽

pp. 159-171

Author(s):

Sourav Santra ◽

Sasti Gopal Das ◽

Suman Kumar Halder ◽

Kuntal Ghosh ◽

Amrita Banerjee ◽

...

Keyword(s):

In Silico ◽

Spike Protein ◽

Vetiveria Zizanioides ◽

Receptor Binding Site ◽

Cassia Angustifolia ◽

Global Pandemic ◽

Therapeutic Molecules ◽

Cymbopogon Martinii ◽

Aconitum Heterophyllum ◽

Justicia Adhatoda

On-going global pandemic COVID-19 has spread all over the world and has led to more than 1.97 million deaths till date. Natural compounds may be useful to protecting health in this perilous condition. Mechanism of shuttle entry of SARS-COV-2 virus is by interaction with viral spike protein with human angiotensin-converting enzyme-2 (ACE-2) receptor. To explore potential natural therapeutics, 213 important phytochemi-cals of nine medicinal plants Aconitum heterophyllum, Cassia angustifolia, Cymbopogon flexuosus, Cymbopogon martinii, Nux vomica, Phyllanthus urinaria, Swertia chirayita, Justicia adhatoda, Vetiveria zizanioides were selected for in-silico molecular docking against the spike protein of SARS-COV-2 and compared with recently prescribed drug chloroquine, ramdesivir, lopinavir and hydroxychloroquine. Results revealed that rhamnocitrin of P. urinaria, 1,5-dihydroxy-3,8-dimethoxyxanthone of S. chirayita and laevojunenol of V. zizanioides potentially binds with the receptor binding site of SARS-COV-2 spike glycoprotein and more robustly destabilized the RBD-ACE-2 binding over chloroquine, ramdesivir, lopinavir and hydroxychloroquine. It was also found that laevojunenol, rhamnocitrin, and 1,5-dihydroxy-3,8-dimethoxyxanthone qualiﬁed the criteria for drug-likeness as per Lipinski rule. After attachment of the selected phytochemical with the spike protein the aﬃnity of the later towards ACE-2 was minimized and the eﬀect of 1,5-dihydroxy-3,8-dimethoxyxanthone and laevojunenol was superior. Hence, rhamnocitrin of P. urinaria, 1,5-dihydroxy-3,8-dimethoxyxanthone of S. chirayita and laevojunenol of V. zizanioides, are potential therapeutic molecules for SARS-COV-2, which upon binding with spike protein changes the aﬃnity of the spike towards ACE-2 and therefore restrict the entry of the virus into a human cell. Subsequent clinical validation is needed to conﬁrm these phytochemicals as drugs to combat COVID-19.

Download Full-text