Maria McCavitt-Malvido

Gladstone Institutes

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Mélanie Ott

Gladstone Institutes

Taha Y. Taha

Gladstone Institutes

Mauricio Montaño

Gladstone Institutes

Irene P. Chen

Gladstone Institutes

Nevan J. Krogan

Gladstone Institutes

G.J. Correy

University of California, San Francisco

Manasi P. Jogalekar

UCSF Helen Diller Family Comprehensive Cancer Center

Patrick C. O’Leary

UCSF Helen Diller Family Comprehensive Cancer Center

Morgan E. Diolaiti

University of California, San Francisco

Alan Ashworth

UCSF Helen Diller Family Comprehensive Cancer Center

Cooperative Institutions

University of California, San Francisco

Gladstone Institutes

Quantitative BioSciences

University of California, Berkeley

Mapp Biopharmaceutical (United States)

University of California System

QB3

Universidad Católica de Santa Fe

UCSF Helen Diller Family Comprehensive Cancer Center

Chan Zuckerberg Initiative (United States)

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Reversion of Ebolavirus Disease from a Single Intramuscular Injection of a Pan-Ebolavirus Immunotherapeutic

Pathogens (2022)

Erin A. Kuang Robert W. Cross Maria McCavitt-Malvido Dafna M. Abelson Viktoriya Borisevich

Intravenous (IV) administration of antiviral monoclonal antibodies (mAbs) can be challenging, particularly during an ongoing epidemic, due to the considerable resources required for performing infusions. An ebolavirus therapeutic administered via intramuscular (IM) injection would reduce the burdens associated with IV infusion and allow rapid treatment of exposed individuals during an outbreak. Here, we demonstrate how MBP134, a cocktail of two pan-ebolavirus mAbs, reverses the course of Sudan ebolavirus disease (Gulu variant) with a single IV or IM dose in non-human primates (NHPs) as late as five days post-exposure. We also investigate the utility of adding half-life extension mutations to the MBP134 mAbs, ultimately creating a half-life extended cocktail designated MBP431. When delivered as a post-exposure prophylactic or therapeutic, a single IM dose of MBP431 offered complete or significant protection in NHPs challenged with Zaire ebolavirus. In conjunction with previous studies, these results support the use of MBP431 as a rapidly deployable IM medical countermeasure against every known species of ebolavirus.

Ebolavirus

10.3390/pathogens11060655

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A single inactivating amino acid change in the SARS-CoV-2 NSP3 Mac1 domain attenuates viral replication in vivo

PLoS Pathogens (2023)

Taha Y. Taha Rahul K. Suryawanshi Irene P. Chen G.J. Correy Maria McCavitt-Malvido

Despite unprecedented efforts, our therapeutic arsenal against SARS-CoV-2 remains limited. The conserved macrodomain 1 (Mac1) in NSP3 is an enzyme exhibiting ADP-ribosylhydrolase activity and a possible drug target. To determine the role of Mac1 catalytic activity in viral replication, we generated recombinant viruses and replicons encoding a catalytically inactive NSP3 Mac1 domain by mutating a critical asparagine in the active site. While substitution to alanine (N40A) reduced catalytic activity by ~10-fold, mutations to aspartic acid (N40D) reduced activity by ~100-fold relative to wild-type. Importantly, the N40A mutation rendered Mac1 unstable in vitro and lowered expression levels in bacterial and mammalian cells. When incorporated into SARS-CoV-2 molecular clones, the N40D mutant only modestly affected viral fitness in immortalized cell lines, but reduced viral replication in human airway organoids by 10-fold. In mice, the N40D mutant replicated at >1000-fold lower levels compared to the wild-type virus while inducing a robust interferon response; all animals infected with the mutant virus survived infection. Our data validate the critical role of SARS-CoV-2 NSP3 Mac1 catalytic activity in viral replication and as a promising therapeutic target to develop antivirals.

Viral protein

Replicon

10.1371/journal.ppat.1011614

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Structure-based discovery of highly bioavailable, covalent, broad-spectrum coronavirus-MPro inhibitors with potent in vivo efficacy

bioRxiv (Cold Spring Harbor Laboratory) (2025)

Tyler C. Detomasi Gilles Degotte Sijie Huang Rahul K. Suryawanshi Amy Diallo

The main protease (MPro) of SARS-CoV-2 is crucial for viral replication and is the target of nirmatrelvir (the active ingredient of Paxlovid) and ensitrelvir. The identification of new agents with differentiated pharmacokinetic and drug resistance profiles will increase therapeutic options for COVID-19 patients and bolster pandemic preparedness generally. Starting with a lead-like dihydrouracil chemotype from a large-library docking campaign, we improved MPro inhibition >1,000 fold by engaging additional subsites in the MPro active site, most notably by employing a latent propargyl electrophile to engage the catalytic Cys145. Advanced leads from this series, including AVI 4516 and AVI 4773 show pan-coronavirus antiviral activity in cells, very low clearance in mice, and for AVI 4773 a rapid reduction in viral titers more than a million fold after just three doses, more rapidly and effectively than the approved drugs, nirmatrelvir and ensitrelvir. Both AVI 4516 and AVI 4773 are well distributed in mouse tissues, including brain, where concentrations ten or fifteen-thousand times the EC90, respectively, are observed eight hours after an oral dose. As exemplar of the series, AVI 4516 shows minimal inhibition of major CYP isoforms and human cysteine and serine proteases, likely due to its latent electrophilic warhead. AVI 4516 also exhibits synergy in cellular infection models in combination with the RdRp inhibitor molnupiravir, while related analogs strongly inhibit nirmatrelvir-resistant MPro mutant virus in cells. The in vivo and antiviral properties of this new chemotype are differentiated from existing clinical and pre-clinical MPro inhibitors, and will advance new therapeutic development against emerging SARS-CoV-2 variants and other coronaviruses.

Broad spectrum

Coronavirus

10.1101/2025.01.16.633443

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The Mac1 ADP-ribosylhydrolase is a Therapeutic Target for SARS-CoV-2

Rahul K. Suryawanshi Priyadarshini Jaishankar G.J. Correy Moira Rachman Patrick C. O’Leary

SARS-CoV-2 continues to pose a threat to public health. Current therapeutics remain limited to direct acting antivirals that lack distinct mechanisms of action and are already showing signs of viral resistance. The virus encodes an ADP-ribosylhydrolase macrodomain (Mac1) that plays an important role in the coronaviral lifecycle by suppressing host innate immune responses. Genetic inactivation of Mac1 abrogates viral replication in vivo by potentiating host innate immune responses. However, it is unknown whether this can be achieved by pharmacologic inhibition and can therefore be exploited therapeutically. Here we report a potent and selective lead small molecule, AVI-4206, that is effective in an in vivo model of SARS-CoV-2 infection. Cellular models indicate that AVI-4206 has high target engagement and can weakly inhibit viral replication in a gamma interferon- and Mac1 catalytic activity-dependent manner; a stronger antiviral effect for AVI-4206 is observed in human airway organoids. In an animal model of severe SARS-CoV-2 infection, AVI-4206 reduces viral replication, potentiates innate immune responses, and leads to a survival benefit. Our results provide pharmacological proof of concept that Mac1 is a valid therapeutic target via a novel immune-restoring mechanism that could potentially synergize with existing therapies targeting distinct, essential aspects of the coronaviral life cycle. This approach could be more widely used to target other viral macrodomains to develop antiviral therapeutics beyond COVID-19.

10.7554/elife.103484.1

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Mild SARS-CoV-2 infection results in long-lasting microbiota instability

bioRxiv (Cold Spring Harbor Laboratory) (2022)

Vaibhav Upadhyay Rahul Suryawanshi Preston Tasoff Maria McCavitt-Malvido G. Renuka Kumar

Viruses targeting mammalian cells can indirectly alter the gut microbiota, potentially compounding their phenotypic effects. Multiple studies have observed a disrupted gut microbiota in severe cases of SARS-CoV-2 infection that require hospitalization. Yet, despite demographic shifts in disease severity resulting in a large and continuing burden of non-hospitalized infections, we still know very little about the impact of mild SARS-CoV-2 infection on the gut microbiota in the outpatient setting. To address this knowledge gap, we longitudinally sampled 14 SARS-CoV-2 positive subjects who remained outpatient and 4 household controls. SARS-CoV-2 cases exhibited a significantly less stable gut microbiota relative to controls, as long as 154 days after their positive test. These results were confirmed and extended in the K18-hACE2 mouse model, which is susceptible to SARS-CoV-2 infection. All of the tested SARS-CoV-2 variants significantly disrupted the mouse gut microbiota, including USA-WA1/2020 (the original variant detected in the United States), Delta, and Omicron. Surprisingly, despite the fact that the Omicron variant caused the least severe symptoms in mice, it destabilized the gut microbiota and led to a significant depletion in Akkermansia muciniphila . Furthermore, exposure of wild-type C57BL/6J mice to SARS-CoV-2 disrupted the gut microbiota in the absence of severe lung pathology.Taken together, our results demonstrate that even mild cases of SARS-CoV-2 can disrupt gut microbial ecology. Our findings in non-hospitalized individuals are consistent with studies of hospitalized patients, in that reproducible shifts in gut microbial taxonomic abundance in response to SARS-CoV-2 have been difficult to identify. Instead, we report a long-lasting instability in the gut microbiota. Surprisingly, our mouse experiments revealed an impact of the Omicron variant, despite producing the least severe symptoms in genetically susceptible mice, suggesting that despite the continued evolution of SARS-CoV-2 it has retained its ability to perturb the intestinal mucosa. These results will hopefully renew efforts to study the mechanisms through which Omicron and future SARS-CoV-2 variants alter gastrointestinal physiology, while also considering the potentially broad consequences of SARS-CoV-2-induced microbiota instability for host health and disease.

Akkermansia muciniphila

Akkermansia

10.1101/2022.12.07.519508

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Therapeutic administration of a cross-reactive mAb targeting the fusion glycoprotein of Nipah virus protects nonhuman primates

Science Translational Medicine (2024)

Larry Zeitlin Robert W. Cross Courtney Woolsey Brandyn R. West Viktoriya Borisevich

No licensed vaccines or therapies exist for patients infected with Nipah virus (NiV), although an experimental human monoclonal antibody (mAb) cross-reactive to the NiV and Hendra virus (HeV) G glycoprotein, m102.4, has been tested in a phase 1 trial and has been provided under compassionate use for both HeV and NiV exposures. NiV is a highly pathogenic zoonotic paramyxovirus causing regular outbreaks in humans and animals in South and Southeast Asia. The mortality rate of NiV infection in humans ranges from 40% to more than 90%, making it a substantial public health concern. The NiV G glycoprotein mediates host cell attachment, and the F glycoprotein facilitates membrane fusion and infection. We hypothesized that a mAb against the prefusion conformation of the F glycoprotein may confer better protection than m102.4. To test this, two potent neutralizing mAbs against NiV F protein, hu1F5 and hu12B2, were compared in a hamster model. Hu1F5 provided superior protection to hu12B2 and was selected for comparison with m102.4 for the ability to protect African green monkeys (AGMs) from a stringent NiV challenge. AGMs were exposed intranasally to the Bangladesh strain of NiV and treated 5 days after exposure with either mAb (25 milligrams per kilogram). Whereas only one of six AGMs treated with m102.4 survived until the study end point, all six AGMs treated with hu1F5 were protected. Furthermore, a reduced 10 milligrams per kilogram dose of hu1F5 also provided complete protection against NiV challenge, supporting the upcoming clinical advancement of this mAb for postexposure prophylaxis and therapy.

Hendra Virus

Post-exposure prophylaxis

10.1126/scitranslmed.adl2055

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Citations (8)