Oral antiviral CD04872SC shows promise in neutralizing COVID-19 variants, offering hope for broad-spectrum treatment

 

Oral antiviral CD04872SC shows promise in neutralizing COVID-19 variants, offering hope for broad-spectrum treatment

In a recent article published in the journal Biomedicines, researchers at the University of Houston College of Pharmacy discuss their discovery of a small molecule drug candidate that could provide immediate protection against infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and markedly shorten the course of illness.

Background

SARS-CoV-2 and its continuously emerging variants, the most recent of which include the Omicron sublineages, continue to cause infections worldwide and threaten patients of all ages. These variants have demonstrated the ease with which this lethal virus can accommodate antigenic changes in its spike (S) protein without losing its replication and immune-evading abilities. Therefore, identifying effective antivirals to combat COVID-19 is crucial.

About the study

In the present study, researchers perform in silico screening of 1,509,984 feature-rich compounds in the small molecule databases of UH Research Computing Data Core to identify top hits against the SARS-CoV-2 S glycoprotein. The top 15 molecules that disrupted the interaction between the S protein and host cell target, the angiotensin-converting enzyme 2 (ACE2) receptor, were selected, evaluated, and ranked in cell-based assays.

To this end, the researchers performed infection inhibition drug screening and cell cytotoxicity assays. Furthermore, the team used a Protein Thermal Shift assay based on differential scanning fluorimetry (DSF) utilizing a specialized fluorogenic dye to analyze stability changes of viral particles in the presence of the lead candidate CD04872SC.

Thermal shift assays quantify variations in temperatures at which a protein denatures, thereby indicating a protein’s stability under varying conditions, such as when it is attached to a drug or encounters varying pH. In the current study, a thermal shift assay was performed to demonstrate the binding between CD04872SC and the S glycoprotein of various SARS-CoV-2 variants.

Results

Molecular dynamic simulations revealed that some of the compounds from the Maybridge and ZINC libraries had favorable interactions with the ACE-2 receptor binding domain (RBD) interface. One small molecule, CD04872SC, formed the closest association in functional in vitro assays using its amide carbonyl and the backbone N of GLY169 at a resolution of 3.1 Å. This compound also established hydrophobic interactions with TYR116, TYR172, and TYR162.

CD04872SC exhibited a half-maximal effective concentration (EC50) of 248 μM and was found to inhibit infection with the SARS-CoV-2 Delta and Omicron variants with EC50 values of 152 μM and 308 μM, respectively. In cell cytotoxicity assays, CD04872SC showed no significant cell cytotoxicity within the tested concentrations.

Real-time melt experiments demonstrated the direct binding between CD04872SC and the S glycoprotein of each tested SARS-CoV-2 variant. The authors also noted a difference of about 3 °C in the stability of the SARS-CoV-2 viral suspensions in the presence of CD04872SC compared to its absence. Delta and Omicron exhibited similar stabilizing tendencies.

Conclusions

To summarize, the current study suggested that in striking contrast to vaccines, neutralizing small molecules could provide immediate protection against SARS-CoV-2 infection, irrespective of the age or immunity status of the individual. Such agents would have higher efficacy in high-risk populations, including immunocompromised individuals who do not adequately produce neutralizing antibodies (nAbs).

Further development of CD04872SC derivatives, including preclinical testing of their effectiveness in animal models, is still warranted to establish these agents as a potential treatment for COVID-19 and a more cost-effective substitute to expensive neutralizing mAb treatments.

International Conference on Infectious Diseases

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TB deadliest infectious disease worldwide after COVID-19 in 2021

The number of deaths from tuberculosis is on the rise as the illness has been recorded as the world's deadliest infectious disease after COVID-19 in 2021, killing 1.6 million people, according to the World Health Organization (WHO).

Tuberculosis is an airborne contagious infection that can affect all tissues and organs such as lungs, bones, eyes and skin. Although it is possible to treat it thanks to scientific studies, tuberculosis continues to claim a serious number of lives across the world every year.

According to the WHO, an estimated 10.6 million people, including 1.2 million children, fell ill with the disease globally and 1.6 million died in 2021.

On March 24 each year, World Tuberculosis Day is observed globally to raise public awareness about the preventable and curable disease.

Tereza Kasaeva, WHO Global Tuberculosis Program director, said 2023 is a critical year to push forward the agenda toward ending the disease, as there are several high-level opportunities to raise visibility, increased political commitment and enhance investments for tuberculosis response.

"The theme of world TB day 2023 'Yes! We can end TB!', reflects this and aims to inspire hope and encourage high-level leadership, increased investments, faster uptake of new WHO recommendations, adoption of innovations, accelerated action, and multisectoral collaboration to combat the TB epidemic," Kasaeva said in a video message.

She said despite global efforts to fight tuberculosis, nearly 4,400 individuals lose their lives on a daily basis, and around 30,000 others become ill, "while global efforts to combat TB have saved an estimated 74 million lives since the year 2000."

People who suffer from undernutrition face a tripled risk compared to others. About 2.2 million cases in 2021 are estimated to be caused due to undernutrition.

More than 80% of deaths from the disease occur in low and middle-income countries.

Although it is seen in every region of the world, South Asia is at the forefront of the regions where tuberculosis was most common in 2021. According to the WHO report, 46% of cases in 2021 were seen in South Asia and 23% in Africa.

The WHO report pointed out that two-thirds of the worldwide tuberculosis cases in 2020 were seen in eight countries – India, Indonesia, China, Philippines, Pakistan, Nigeria, Bangladesh and the Democratic Republic of Congo.

After the WHO declared tuberculosis a "global emergency" in 1993, steps have been taken to combat the disease across the globe.

The United Nations has set one of its sustainable development goals to end the disease by 2030. Furthermore, the WHO has implemented the Tuberculosis Action Plan for the WHO European Region 2023-2030 as part of its end tuberculosis strategy.

The action plan aims to reduce incidence by 80% and deaths by 90% in the WHO European Region, including Türkiye.

Diagnosis and treatment services for tuberculosis are offered free of charge by all health institutions in Türkiye.

All drugs used in the treatment of tuberculosis patients are also supplied by the Health Ministry.

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Pathophysiology | Infectious Diseases Conference |

New, Better Models Show How Infectious Diseases Like COVID-19 Spread

 

New, Better Models Show How Infectious Diseases Like COVID-19 Spread

The COVID-19 pandemic has emphasized the significance of modeling in comprehending the spread of diseases and in providing crucial insights into disease prevention and control. A new model has utilized COVID-19 data and combined two classic methodologies to enhance predictions about disease spread.

A widely used modeling technique involves dividing the population into compartments, such as susceptible (S), infected (I), and recovered (R), in what is known as the SIR model. This approach models the rates of change that describe the movement of individuals from one compartment to another.


KAUST researchers, led by Paula Moraga, integrated SIR compartment modeling in time and a point process modeling approach in space–time, while also taking into account age-specific contact patterns. To do this, they used a two-step framework that allowed them to model data on infectious locations over time for different age groups.

“The model gives more accurate predictions than previous approaches when making short/mid-range predictions in space and time,” says lead researcher André Amaral.

Their approach paid off. In a simulation study to assess the model’s performance, and in a case study of COVID-19 cases in Cali, Colombia, the model performed better when making predictions and provided similar results for past time points, compared with models commonly used in predictive modeling.

“The model’s features can help decision-makers to identify high-risk locations and vulnerable populations to develop better strategies for disease control,” says Amaral.

It also can be used with any infectious disease that fits the compartment model assumptions, such as influenza. Furthermore, the model can account for different age groups and their associated contact patterns, meaning it allows more detailed conclusions about where, when, and to which population group decision-makers should focus their resources if they want to control disease spread.

“In future work, we might extend such an approach and use different temporal models to replace the SIR model. This would allow us to account for different epidemic dynamics and expand the number of scenarios that the model can be used for,” says Amaral.

“Finally, to improve the model’s predictive capabilities, we might work on developing ensemble approaches that combine a number of predictions from a number of different models and also account for potential time delays in collecting data,” he adds.

Moraga says the model’s performance demonstrates the importance of quality and detailed data by location, time, and population group to understand infectious disease dynamics while highlighting the need to strengthen national surveillance systems to improve public health decision-making.

Reference: “Spatio-temporal modeling of infectious diseases by integrating compartment and point process models” by André Victor Ribeiro Amaral, Jonatan A. González and Paula Moraga, 13 December 2022, Stochastic Environmental Research and Risk Assessment.

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The Fractal Geometry of Alzheimer’s disease

International Conference on Infectious Diseases

The International Conference on Infectious Diseases is an event that brings together researchers, clinicians, public health professionals, and other experts from around the world to discuss the latest developments and challenges in the field of infectious diseases. The conference typically features keynote speakers, plenary sessions, and poster presentations covering a wide range of topics related to infectious diseases, including epidemiology, diagnosis, treatment, and prevention. The conference is usually held annually and is organized by different institutions, including academic institutions, research organizations, and public health agencies. The conference provides a platform for researchers and professionals to share their knowledge and exchange ideas, foster collaborations, and explore new research opportunities. Attending the International Conference on Infectious Diseases can be beneficial for researchers, clinicians, and other professionals working in the field of infectious diseases, as it provides an opportunity to stay up-to-date on the latest research and trends in the field, network with peers and experts, and collaborate on new research projects.

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Biology of SARS-CoV-2: Infection | Infectious Diseases Conferences |