Time to ‘Mind the Gap’ in novel small molecule drug discovery for direct-acting antivirals for SARS-CoV-2

Jonsson, Colleen B.; Golden, Jennifer E.

doi:10.1016/j.coviro.2021.06.008

Cited by 10 publications

(4 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The morbidity and mortality associated with the COVID-19 pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) are continuing to have a major impact on public health and the global economy. − The timely discovery and introduction into the clinic of effective vaccines and monoclonal antibodies have ameliorated the impact and threat of the disease; , however, there is a pressing need for the development of effective and complementary countermeasures, including an expanded and diversified portfolio of direct-acting antivirals (DAAs) − that can be rapidly deployed against SARS-CoV-2 and variants, as well as emerging and re-emerging coronaviruses. , …”

mentioning

confidence: 99%

Broad-Spectrum Cyclopropane-Based Inhibitors of Coronavirus 3C-like Proteases: Biochemical, Structural, and Virological Studies

Dampalla

Nguyen

Rathnayake

et al. 2022

ACS Pharmacol. Transl. Sci.

View full text Add to dashboard Cite

The advent of SARS-CoV-2, the causative agent of COVID-19, and its worldwide impact on global health, have provided the impetus for the development of effective countermeasures that can be deployed against the virus, including vaccines, monoclonal antibodies, and direct-acting antivirals (DAAs). Despite these efforts, the current paucity of DAAs has created an urgent need for the creation of an enhanced and diversified portfolio of broadly acting agents with different mechanisms of action that can effectively abrogate viral infection. SARS-CoV-2 3C-like protease (3CL pro ), an enzyme essential for viral replication, is a validated target for the discovery of SARS-CoV-2 therapeutics. In this report, we describe the structure-guided utilization of the cyclopropane moiety in the design of highly potent inhibitors of SARS-CoV-2 3CL pro , SARS-CoV-1 3CL pro , and MERS-CoV 3CL pro . High-resolution cocrystal structures were used to identify the structural determinants associated with the binding of the inhibitors to the active site of the enzyme and unravel the mechanism of action. Aldehydes 5c and 11c inhibited SARS-CoV-2 replication with EC 50 values of 12 and 11 nM, respectively. Furthermore, the corresponding aldehyde bisulfite adducts 5d and 11d were equipotent with EC 50 values of 13 and 12 nM, respectively. The safety index (SI) values for compounds 5c/11c and 5d/11d ranged between 7692 and 9090. Importantly, aldehydes 5c/11c and bisulfite adducts 5d/11d potently inhibited MERS-CoV 3CL pro with IC 50 values of 80 and 120 nM, and 70 and 70 nM, respectively. Likewise, compounds 5c/11c and 5d/11d inhibited SARS-CoV-1 with IC 50 values of 960 and 350 nM and 790 and 240 nM, respectively. Taken together, these studies suggest that the inhibitors described herein have low cytotoxicity and high potency and are promising candidates for further development as broad-spectrum direct-acting antivirals against highly pathogenic coronaviruses.

show abstract

mentioning

confidence: 99%

Broad-Spectrum Cyclopropane-Based Inhibitors of Coronavirus 3C-like Proteases: Biochemical, Structural, and Virological Studies

Dampalla

Nguyen

Rathnayake

et al. 2022

ACS Pharmacol. Transl. Sci.

View full text Add to dashboard Cite

show abstract

“…Compounds in the EEV pipeline have advanced further and with greater characterization than in previous years, as exemplified by EIDD-1931, which progressed within the EEV pipeline until a strategic pivot to SARS-CoV-2 was implemented, resulting in the emergency use authorization of Molnupiravir [ 191 ]. In fact, the global impact of COVID-19 has highlighted a gap in the availability and development of anti-infective agents for viruses that pose a significant threat or have pandemic potential [ 192 , 193 ]. Consequently, funding initiatives have been established to support efforts in this area which includes the Togaviridae EEVs, VEEV and EEEV, as viruses of concern.…”

Section: Discussionmentioning

confidence: 99%

Advances in the Development of Small Molecule Antivirals against Equine Encephalitic Viruses

Ogorek

Golden

2023

Viruses

Self Cite

View full text Add to dashboard Cite

Venezuelan, western, and eastern equine encephalitic alphaviruses (VEEV, WEEV, and EEEV, respectively) are arboviruses that are highly pathogenic to equines and cause significant harm to infected humans. Currently, human alphavirus infection and the resulting diseases caused by them are unmitigated due to the absence of approved vaccines or therapeutics for general use. These circumstances, combined with the unpredictability of outbreaks—as exemplified by a 2019 EEE surge in the United States that claimed 19 patient lives—emphasize the risks posed by these viruses, especially for aerosolized VEEV and EEEV which are potential biothreats. Herein, small molecule inhibitors of VEEV, WEEV, and EEEV are reviewed that have been identified or advanced in the last five years since a comprehensive review was last performed. We organize structures according to host- versus virus-targeted mechanisms, highlight cellular and animal data that are milestones in the development pipeline, and provide a perspective on key considerations for the progression of compounds at early and later stages of advancement.

show abstract

“…DAA commonly targets viral entry and fusion, or key enzymes like viral polymerases and proteases such as the SARS-CoV2 3-chymotrypsin-like protease (3CL pro ), also known as main protease (M pro ), and papain-like protease (PL pro ) [ 36 , 38 ]. By targeting viral replication directly, DAA are generally thought to have fewer side effects than HTA [ 39 ]. However, by targeting the virus directly, DAA are known to cause mutations that can lead to reduced drug efficacy and drug resistance [ 40 , 41 ].…”

Section: Directly Acting Antivirals (Daa)mentioning

confidence: 99%

An Update on SARS-CoV-2 Clinical Trial Results—What We Can Learn for the Next Pandemic

Arman,

Brun,

Hill

et al. 2023

IJMS

View full text Add to dashboard Cite

The coronavirus disease 2019 (COVID-19) pandemic has claimed over 7 million lives worldwide, providing a stark reminder of the importance of pandemic preparedness. Due to the lack of approved antiviral drugs effective against coronaviruses at the start of the pandemic, the world largely relied on repurposed efforts. Here, we summarise results from randomised controlled trials to date, as well as selected in vitro data of directly acting antivirals, host-targeting antivirals, and immunomodulatory drugs. Overall, repurposing efforts evaluating directly acting antivirals targeting other viral families were largely unsuccessful, whereas several immunomodulatory drugs led to clinical improvement in hospitalised patients with severe disease. In addition, accelerated drug discovery efforts during the pandemic progressed to multiple novel directly acting antivirals with clinical efficacy, including small molecule inhibitors and monoclonal antibodies. We argue that large-scale investment is required to prepare for future pandemics; both to develop an arsenal of broad-spectrum antivirals beyond coronaviruses and build worldwide clinical trial networks that can be rapidly utilised.

show abstract

Time to ‘Mind the Gap’ in novel small molecule drug discovery for direct-acting antivirals for SARS-CoV-2

Cited by 10 publications

References 46 publications

Broad-Spectrum Cyclopropane-Based Inhibitors of Coronavirus 3C-like Proteases: Biochemical, Structural, and Virological Studies

Broad-Spectrum Cyclopropane-Based Inhibitors of Coronavirus 3C-like Proteases: Biochemical, Structural, and Virological Studies

Advances in the Development of Small Molecule Antivirals against Equine Encephalitic Viruses

An Update on SARS-CoV-2 Clinical Trial Results—What We Can Learn for the Next Pandemic

Contact Info

Product

Resources

About