Publisher Health

If you remember your first hit on a cigarette, you know how sickening nicotine can be. Yet, for many people, the rewards of nicotine outweigh the negative effects of high doses.
University of California, Berkeley, researchers have now mapped out part of the brain network responsible for the negative consequences of nicotine, opening the door to interventions that could boost the aversive effects to help people quit smoking.
Though most addictive drugs at high doses can cause physiological symptoms that lead to unconsciousness or even death, nicotine is unique in making people physically ill when inhaled or ingested in large quantities. As a result, nicotine overdoses are rare, though the advent of e-cigarettes has made “nic-sick” symptoms like nausea and vomiting, dizziness, rapid heartbeat and headaches more common.
The new research, conducted in mice, suggests that this aversive network could be manipulated to treat nicotine dependence.
“Decades of research have focused on understanding how nicotine reward leads to drug addiction and what are the underlying brain circuits. In contrast, the brain circuits that mediate the aversive effects of nicotine are largely understudied,” said Stephan Lammel, UC Berkeley associate professor of molecular and cell biology. “What we found is that the brain circuits that are activated after a high aversive dose are actually different from those that are activated when nicotine is delivered at a low dose. Now that we have an understanding of the different brain circuits, we think we can maybe develop a drug so that, when nicotine is taken at a low dose, these brain circuits can be coactivated to induce an acute aversive effect. This could actually be a very effective treatment for nicotine addiction in the future, which we currently do not have.”
Lammel and Christine Liu, who recently obtained her Ph.D. from UC Berkeley, also found that nicotine receptors in the reward pathway become desensitized by high doses of nicotine, which probably contributes to the negative experience of high doses.

Racial and ethnic minorities bore a disproportionate mental health burden during the COVID-19 pandemic, according to a new study published this week in the open-access journal PLOS ONE by Andrew Chan of Harvard Medical School, Tim Spector of King’s College London, and colleagues.
Previous research has established that minorities have borne a disproportionate COVID-19 burden, including higher rates of infection, severe disease, hospitalization and death, when compared to non-Hispanic whites. Moreover, a three-fold increase in the incidence of depression symptoms has been reported in the wake of the pandemic. However, the effects of COVID-19 on the mental health of minorities were unclear.
In the new study, the researchers used data on 691,473 people in the U.S. and U.K. who responded to the smartphone-based COVID Symptom Study between January 23, 2021 and June 9, 2021. Participants were recruited through social media, reported baseline information and then logged daily information on symptoms and COVID-19 testing results using the Zoe app. Questions were included from the PHQ-4 (Panvalidated 4-item Patient Health Questionnaire for Depression and Anxiety), PHQ-9 and the GAD-7 (7-item General Anxiety Disorder) screening tools.
The study found that, after controlling for personal factors including prior mental health diagnoses and changes in leisure time activities, Black participants in the U.S. were 1.16 times more likely to screen positive for depression than White participants (95% CI 1.02-1.31). Compared to White participants, Hispanic participants in the U.S. were 1.23 times more likely to screen positive for depression (95% CI 1.11-1.36) and 1.23 times more likely to show signs of anxiety (95% CI 1.12-1.34). Similar results were seen for Black and Asian participants in the U.K. as well as within other subgroups of participants including Black healthcare workers, who had higher odds of depression and anxiety than White healthcare workers.
The authors conclude that minority communities in both the U.S. and U.K. have been disproportionately impacts by the mental health burden of COVID-19 and stand to suffer well beyond any presumed conclusion of the pandemic.
The authors add: “The early phase of COVID-19 pandemic was incredibly disruptive to everyday life. We found that racial and ethnic minorities in the U.S. and U.K. were more likely to screen positive for depression and anxiety. This suggests a disproportionate impact and mental health burden on persons of color, which need to be considered as we reshape health care systems to prioritize the long-term consequences of this disease.”
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The number of privately insured adults in the United States prescribed opioid medications for cancer pain and for chronic non-cancer pain declined between 2012 and 2019, according to a new study published this week in the open-access journal PLOS ONE by Sachini Bandara and Emma McGinty of Johns Hopkins Bloomberg School of Public Health and Mark Bicket of the University of Michigan.
Over the past decade, governments, health systems and insurers have issued clinical guidelines designed to reduce opioid prescribing. Previous studies have found that overall U.S. opioid prescribing rates decreased between 2010 and 2020. However, U.S. recommendations on opioids specifically exempt individuals in active cancer treatment from the limits.
In the new study, the researchers used the IBM MarketScan Research Databases from 2012 to 2019, which include health insurance claims and encounters for 26.1 to 53.1 million individuals covered by approximately 100 private insurance companies in the U.S. For each calendar year, the team identified individuals with a cancer diagnosis or a chronic non-cancer pain diagnosis, including low back pain, neuropathic pain, headaches, or arthritis.
Over the time period studied, the proportion of people who received any opioid prescription dropped from 49.7% to 30.5% for people with chronic non-cancer pain and from 86.0% to 78.7% for people with cancer. At the same time, rates of non-opioid pain medication remained steady for people with non-cancer pain (66.7% to 66.4%) and increased for cancer patients (74.4% to 78.8%). Among those prescribed opioids, fewer received extremely high doses or more than a week supply.
The researchers conclude that opioid prescribing has declined for both chronic non-cancer pain and cancer pain, without corresponding substitution of non-opioid therapies to manage pain. Further work is needed to examine how the changes have influenced the management of pain patients in both groups, they say.
The authors add: “We find that from 2012-2019 there were declines in opioid prescribing for individuals with chronic non-cancer pain and individuals with cancer without corresponding increases in receipt of non-opioid therapies. These findings highlight the need to better understand how declines in prescribing are influencing the management of pain among these patient populations, particularly as the CDC is currently updating opioid prescribing guidelines for chronic pain.”
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An analysis of scholarly research papers published in the last 50 years provides new insights into trends in research productivity, highlighting an overall increase in productivity and a worldwide gender gap. Milad Haghani of the University of New South Wales in Sydney, Australia, and colleagues present these findings in the open-access journal PLOS ONE on August 10, 2022.
Tracking trends in research productivity can help inform many endeavors, such as allocating research funding, making hiring decisions, and maximizing the impact of research.
To build an updated picture of productivity trends, Haghani and colleagues conducted a deep-dive search of scholarly publications using the Web of Science platform. They ultimately analyzed information on 75 million scholarly articles published worldwide between 1970 and 2020. In line with prior evaluations, they used the number of scholarly publications as a measure of research productivity.
This analysis illuminated several trends. Between 2010 to 2020, the yearly number of publications generally increased every year, with the fastest-growing fields being environmental sciences and environmental engineering. However, the overall number of publications dropped in 2020, potentially reflecting the impact of the COVID-19 pandemic; computer science, engineering, and social science had the most notable 2020 declines.
The analysis also highlighted a persistent worldwide gap in the overall number of publications involving at least one female author versus at least one male author, which does not appear to be closing for any country and is widening in some — particularly in Middle Eastern countries. However, the ratio of female-to-male productivity does appear to be narrowing, albeit at very different rates for different countries.
The analysis did not find any significant gender difference in the overall decline in productivity associated with the COVID-19 pandemic. However, in certain countries — including the Netherlands, the U.S., and Germany — the pandemic was associated with a greater decline in male versus female productivity.
The authors note that the long-term impact of the pandemic remains to be determined. They also outline potential directions for future evaluations to further deepen understanding of research productivity trends, such as evaluating gender gaps in specific fields and the impact of country-specific lockdown measures.
The authors add: “The problem of gender gap in scholarly publications, as an indicator of gender representation in academia, is vastly different across the world. In many countries, it is not on its way to closing, and in many others, the trends indicate that the gap will not close even a century from now, unless interventions are introduced.”
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A team led by UT Southwestern researchers has identified how SARS-CoV-2, the virus that causes COVID-19, builds a structure called the RNA cap that’s critical for successful viral replication. The finding, published in Nature, could lead to new strategies to attack COVID-19, which has sickened nearly 600 million and killed more than 6 million worldwide thus far.
“We’re very excited to exploit and make drugs against this protein domain to inhibit RNA cap formation, which, if successful, could offer a whole new approach to treat COVID-19,” said study leader Vincent Tagliabracci, Ph.D., Associate Professor of Molecular Biology, the Michael L. Rosenberg Scholar in Medical Research at UTSW, and a Howard Hughes Medical Institute Investigator.
SARS-CoV-2 uses the genetic molecule ribonucleic acid, or RNA, to provide instructions to infected host cells to build more copies of the virus. A molecular cap on one end of the viral RNA serves multiple functions to accomplish this goal, Dr. Tagliabracci explained. It hides the RNA from the host cell’s immune system, protects it from attack by exonucleases, or cellular enzymes that degrade it, and recruits cellular factors that use the RNA to make viral proteins. If the virus is missing this RNA cap, he said, these processes cease and infection can’t continue.
The new study suggests that the SARS-CoV-2 NiRAN domain, a portion of a viral protein called nsp12, is involved in synthesizing the RNA cap. The NiRAN domain is a pseudokinase, a class of enzymes that are the major focus of the Tagliabracci lab. Experiments showed that the NiRAN domain transfers the viral RNA to another SARS-CoV-2 protein called nsp9 to create a RNA-protein intermediate that is crucial for cap formation.
Dr. Tagliabracci said that he and his colleagues are investigating ways to stymie SARS-CoV-2’s NiRAN domain function, which could eventually lead to a new class of drugs to fight COVID-19.
“In the long-term fight against COVID, we will need antivirals targeting different parts and aspects of the viral life cycle,” he said. “Adding a capping inhibitor would be a nice addition to that arsenal.”
Other researchers who contributed to this study include Gina J. Park, an M.D./Ph.D. candidate in the Medical Scientist Training Program; Adam Osinski, a student in the Graduate School of Biomedical Sciences; Genaro Hernandez, Jennifer L. Eitson, Abir Majumdar, Krzysztof Pawlowski, Zhe Chen, Yang Li, and John W. Schoggins of UTSW; and Marco Tonelli and Katie Henzler-Wildman of the University of Wisconsin-Madison.
This study was funded by the W. M. Keck Foundation, the National Institutes of Health (R01GM135189 and 1DP1AI158124), The Welch Foundation (I-1911), the Life Sciences Research Foundation, and the Polish National Agency for Scientific Exchange (PPN/BEK/2018/1/00431).
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COVID-19 infection in pregnant women is associated with increased risk of adverse outcomes compared to women who are not pregnant, according to a review published in JACC: Advances from the American College of Cardiology Cardiovascular Disease in Women Committee. Cardiovascular complications include heart attack, arrythmias, heart failure and long-haul symptoms that may be difficult to distinguish from other cardiac complications of pregnancy and require the cardiovascular care team to be vigilant when assessing pregnant women with COVID-19.
As COVID-19 cases increased globally, awareness of cardiovascular complications also increased, especially in certain high-risk populations. Heart attacks is estimated in up to 12% of patients. The Centers for Disease Control and Prevention (CDC) found pregnant women are at increased risk of adverse outcomes with COVID-19, including severe infection (10%), ICU admission (4%), mechanical ventilation (3%) and use of ECMO hemodynamic support (0.2%), compared with non-pregnant women of reproductive age. Additionally, pregnant patients who were of increased maternal age, high body mass index or had other pre-existing conditions such as chronic hypertension, pre-eclampsia and pre-existing diabetes, were at even higher risk for severe infection.
When compared to pregnant women without COVID-19, pregnant COVID-19 patients were at higher risk for pre-term birth and stillbirth. Overall, 33% of infants born to patients with COVID-19 were admitted to the neonatal intensive care unit. No other differences have been found for perinatal outcomes.
A U.S. specific study found substantial racial disparities in outcomes for pregnant COVID-19 patients. While non-Hispanic Black women accounted for 14.1% of the study cohort, they represented 26.5% of pregnancy-associated deaths. Pregnancy was associated with a 2.4 times risk of death in Hispanic women with COVID-19 and pregnant Asian and Native Hawaiian/Pacific Islanders were among the highest risks of ICU admissions.
According to the authors, a reason for increased risk of cardiovascular complications is the low vaccination rate in pregnant women compared to other groups. In a recent study of over 130,000 pregnant people over three quarters of those requiring hospital admission, the vast majority of patients requiring critical care and all fetal deaths occurred in unvaccinated compared with vaccinated women
“Pregnant people need to know that they are increased risk of a severe COVID-19 infection, including ICU admissions, cardiac complications, need for critical care and death for the patient or fetus. Unfortunately, pregnant women have lagged behind other groups getting vaccinated,” said Joan Briller, MD, a cardiologist and professor of clinical obstetrics and gynecology at the University of Illinois at Chicago and the study’s lead author. “Available data support vaccination in pregnancy with good safety profile and protective transfer to neonates. The CDC, American College of Obstetrics and Gynecology and Society of Maternal Fetal Medicine among others recommend vaccination in pregnancy. I believe we should support this recommendation with our patients.”
The management of cardiac complications and diagnosis in pregnant COVID-19 patients can be challenging given the overlap of COVID-19 symptoms, cardiovascular disease and pregnancy. According to the authors, imaging findings and timing of presentation may be helpful in differentiation and determining diagnosis. Clinicians may also need to adjust medical therapy during pregnancy and lactation.
The authors suggest management of cardiac complications in pregnant COVID-19 patients requires the creation of a “Pregnancy Heart Team” to optimize care, which may include providers comfortable with high-risk pregnancy, obstetric anesthesia, cardiology, critical care and neonatal care, depending on the nature of the complication, stage of pregnancy and severity of infection.
“Recognition of cardiovascular complication is hampered by failure to include pregnant women in clinical trials despite calls for inclusion of pregnant populations,” Briller said. “Consequently, women may be undertreated or inadequately treated due to lack studies addressing safety and efficacy of therapies during pregnancy or conversely be exposed to therapies where safety is not known.”
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As the world has witnessed firsthand, SARS-CoV-2, the virus that causes COVID, is difficult to control because of its ability to rapidly mutate and produce many different variants. Scientists at Scripps Research have now identified antibodies that are effective against many different SARS-CoV-2 variants, as well as other SARS viruses like SARS-CoV-1, the highly lethal virus that caused an outbreak in 2003. The results showed that certain animals are surprisingly more able to make these types of “pan-SARS virus” antibodies than humans, giving scientists clues as to how to make better vaccines.
The findings, published today in Science Translational Medicine, reveal the antibody structures that produce this more comprehensive immune response. They found these neutralizing antibodies recognize a viral spike region that is relatively more conserved, meaning that it is present across many different SARS viruses and is therefore less likely to mutate over time. This discovery can inform how to develop next-generation vaccines that can offer additional protection against emerging SARS-CoV-2 variants and other SARS-related viruses.
“If we can design vaccines that elicit the similar broad responses that we’ve seen in this study, these treatments could enable broader protection against the virus and variants of concern,” says senior author Raiees Andrabi, PhD, an investigator in the Department of Immunology and Microbiology.
In the study, rhesus macaque monkeys were immunized with the SARS-CoV-2 spike protein-the outside portion on the virus that allows it to penetrate and infect host cells. Two shots were administered, resembling a similar strategy used with currently available mRNA vaccines in humans. Unlike these vaccines, however, the macaques were shown to have a broad neutralizing antibody response against the virus-including variants such as Omicron.
Intrigued by this stark difference, the scientists then collaborated with Ian Wilson’s lab at Scripps Research to investigate the antibody structures. They found these antibodies recognize a conserved region on the edge of the site where the spike protein binds to host cells, called the angiotensin converting enzyme 2 (ACE2) receptor binding site. This is different than the region where the majority of human antibodies target, which overlaps more with the ACE2 receptor binding site and is more variable to change.
“The antibody structures reveal an important area common to multiple SARS-related viruses. This region to date has rarely been seen to be targeted by human antibodies and suggests additional strategies that can be used to coax our immune system into recognizing this particular region of the virus,” says co-senior author Ian Wilson, DPhil, Hansen Professor of Structural Biology and Chair of the Department of Integrative Structural and Computational Biology.
It’s important to note that the macaque’s gene coding for these broad neutralizing antibodies — known as IGHV3-73 — is not the same in humans. The dominant immune response in humans is related to the IGHV3-53 gene, which produces a potent but much narrower neutralizing antibody response. However, the scientists say this discovery opens the door to rationally design and engineer vaccines or vaccine-adjuvant combinations that elicit more broad protection against SARS-CoV-2 and its many variants.
“According to our study, the macaques have an antibody gene that offers them more protection against SARS viruses. This observation teaches us that studying the effect of a vaccine in monkeys can only take us so far but also reveals a new target for our vaccine efforts that we might be able to exploit by advanced protein design strategies,” adds Dennis Burton, PhD, co-senior author and chair of the Department of Immunology and Microbiology.
Because the genetics do differ, Andrabi urges that more investigation is needed — not only for identifying new strategies against SARS viruses, but also for making sure scientists are using the best translational models for their research.
In addition to Andrabi, Wilson and Burton, authors of the study, “Broadly neutralizing antibodies to SARS-related viruses can be readily induced in rhesus macaques,” include Wan-ting He, Meng Yuan, Sean Callaghan, Rami Musharrafieh, Ge Song, Nathan Beutler, Wen-Hsin Lee, Peter Yong, Jonathan L. Torres, Panpan Zhou, Fangzhu Zhao, Xueyong Zhu, Linghang Peng, Deli Huang, Fabio Anzanello, James Ricketts, Mara Parren, Elijah Garcia, David Nemazee, Bryan Briney and Andrew B. Ward of Scripps Research; Murillo Silva and Mariane Melo of Massachusetts Institute of Technology (MIT); Melissa Ferguson and William Rinaldi of Alpha Genesis; Stephen A. Rawlings, Davey M. Smith and Yana Safonova of University of California, San Diego (UCSD); Thomas F. Rogers of Scripps Research and UCSD; Jennifer M. Dan and Alessandro Sette of UCSD and La Jolla Institute for Immunology; Zeli Zhang and Daniela Weiskopf of La Jolla Institute for Immunology; Shane Crotty of UCSD and the La Jolla Institute for Immunology; and Darrell J. Irvine of MIT and Howard Hughes Medical Institute.
This work and the researchers involved were supported by funding by NIH CHAVD UM1 AI44462 (to D.R.B., A.B.W., and I.A.W.), the IAVI Neutralizing Antibody Center, the Bill and Melinda Gates Foundation OPP1170236 and INV-004923 (to I.A.W., A.B.W., and D.R.B.), the Translational Virology Core of the San Diego Center for AIDS Research (CFAR) grant NIH AI036214 (to D.M.S.), NIH 5T32AI007384 (to S.A.R.), and the John and Mary Tu Foundation and the James B. Pendleton Charitable Trust (to D.R.B.). D.H. and D.N. were supported in part by R01AI073148.

A stretch of DNA that hops around the human genome plays a role in premature aging disorders, scientists at the Salk Institute and King Abdullah University of Science and Technology (KAUST) in Saudi Arabia have discovered. In people with early aging, or progeria, RNA encoded by this mobile DNA builds up inside cells. What’s more, the scientists found that blocking this RNA reverses the disease in mice.
The findings, published in Science Translational Medicine on August 10, 2022, focus on a piece of RNA known as LINE-1.
“These findings provide new insight into progeroid syndromes and how to treat them, while also highlighting the importance of LINE-1 RNA in normal aging,” says co-corresponding author Juan Carlos Izpisua Belmonte, a professor in Salk’s Gene Expression Laboratory and director of the Altos Labs San Diego Institute of Science.
Progeroid syndromes, which include Hutchinson-Gilford progeria syndrome and Werner syndrome, cause accelerated aging in children and adolescents. Patients develop not only striking physical appearances but also symptoms and diseases typically associated with older age, such as heart disease, cataracts, type 2 diabetes, osteoporosis and cancer. There are currently no effective treatments for progeroid syndromes.
Izpisua Belmonte and his colleagues knew that one of the molecular signatures of both normal aging and progeroid syndromes is the altered overall organization of DNA. When DNA is packaged differently into the nuclei of cells, it changes which genes are accessible for the cell to use and can therefore drastically change a cell’s behavior and function.
Scientists also knew that human genomes contain hundreds of LINE-1 elements that propagate and move around the genome, as well as encode LINE-1 RNA. The function of these elements is poorly understood, but they change and multiply with age, as well as in diseases including cancer and cardiovascular disease. Izpisua Belmonte’s team wondered whether they also changed in progeroid syndromes.

Stimulator of interferon genes, or STING, helps regulate immune activation. Thus, drugs that activate STING are being tested as a form of cancer immunotherapy and for treating certain infections. Findings from this study reveal previously unknown functional links between STING signaling and immunometabolism. They also suggest that positron emission tomography (PET) imaging could provide a widely accessible approach to measure the pharmacodynamic effects of using STING-activating drugs.
Oral and IV administration of STING-activating drugs stimulate potent anti-tumor responses in mouse models of cancer, suggesting this as a possible strategy for human therapy. Until now, however, researchers have not had a way to determine the magnitude, duration and location of immune activation. This research, led by UCLA Jonsson Comprehensive Cancer Center investigators, investigated whether systemic STING activation induces metabolic alterations in immune cells that can be visualized by PET imaging.
Lab mice were treated with systemic STING agonists and later imaged with PET scans using standard fluorodeoxyglucose (FDG) radiotracing. Immune cells from the spleen were analyzed by RNA sequencing and flow cytometry. The amount of tracer in B and T lymphocytes was measured. In mice bearing prostate or pancreas cancer tumors, the effects of STING agonist treatment on tracer uptake, T-lymphocyte activation marker levels, and tumor growth were evaluated.
Systemic delivery of STING-activating drugs in mice significantly increased PET tracer uptake in the spleen. Analyses of immune cells indicated an increase of tracer in both T and B lymphocytes correlated with the induction of immune cell activation markers. In tumor-bearing mice, STING agonist administration significantly delayed tumor growth and increased radiotracer uptake in secondary lymphoid glands. In addition to identifying previously unknown functional links between STING signaling and immunometabolism, the study suggests that readily available PET scanning could enable a whole-body analysis of the effects of systemic STING-activating therapy in humans. This could potentially provide a diagnostic tool guiding clinical development of this treatment approach.
“A new generation of STING agonists have broadened the available routes of administration to include systemic immune activation and are thus moving quickly in the clinical setting of cancer immunotherapy,” said co-first co-author Hailey Lee, a graduate student in the laboratory of Dr. Caius Radu, a professor in the Molecular and Medical Pharmacology and Surgery Departments at UCLA and a member of the UCLA Jonsson Comprehensive Cancer Center.
Radu, the article’s senior author, said, “Given that overstimulation of the immune system could lead to potential toxic side effects for STING agonists, significant questions remain in regard to optimizing the correct dose and treatment schedule for individual patients. Our recent investigation into the identification of a clinically applicable biomarker highlights PET as a readout for measuring STING agonist-induced immune activation in both the preclinical and clinical settings.”
Co-first author Thuc Le, an adjunct professor of molecular and medical pharmacology at UCLA, added, “Such imaging tools can guide the dosing and scheduling of STING agonists to minimize the risk of immune overstimulation while still retaining therapeutic efficacy. We hope our findings will impact the clinical application of STING agonists.”
Co-first authors Thuc Le and Hailey Lee are UCLA researchers, as are Evan Abt, Khalid Rashid, Amanda Creech, Liu Wei, Amanda Labora, Charlotte Chan, Eric Sanchez, Daniel Karin, Luyi Li, Nanping Wu, Christine Mona, Giuseppe Carlucci, Willy Hugo, Ting-Ting Wu, Timothy Donahue, Johannes Czernin, and corresponding author Caius Radu. Keke Liang is with China Medical University in Shenyang, China. Jing Cui is with Huazhong University of Science and Technology in Hubei, China. Arthur Cho is with Yonsei University College of Medicine in Seoul, South Korea. Kriti Kriti is with Elucidata Corp. in Cambridge, Massachusetts.

A new study, led by researchers from the University of California, Irvine and the University of California, San Diego, reveals a new computation-guided approach to identify small molecules that can restore aspects of wild-type p53 tumor suppression function to mutated p53, which play an important role in many human cancers. This approach was successful both in vitro and in vivo. This strategy can increase chemical diversity of p53 corrector molecules for clinical development.
The tumor suppressor p53 is one of the most powerful mechanisms organisms use to protect themselves from cancer. Elephants have multiple copies of the p53 gene and rarely get cancer. Humans have only one copy and it is the most mutated gene found in human cancer. Diverse therapeutic approaches are actively pursued to target this pathway.
“Interestingly, a large fraction of p53 alterations are missense mutations, where the genetic code of the p53 is altered in a way that produces a different amino acid than it would normally,” explained Peter Kaiser, PhD, professor and chair of the Department of Biological Chemistry at the UCI School of Medicine. “This results in abundance of mutant p53 protein levels in tumors that are, in principle, amenable to a corrector drug approach.”
Published inCell Chemical Biology, the studyidentified small drug-like compounds that act through a well-defined mode of action; do not require covalent attachment, induction of redox imbalance, or metal binding; and have selective anti-cancer activities on tumors with p53 missense mutations. This research provides a framework for p53 reactivation compound discovery that can help to increase chemical diversity and improve pharmacological properties necessary for translation of pharmaceutical p53 mutant reactivation to the clinic.
“This study successfully demonstrates the feasibility and efficacy of pharmaceutical reactivation of mutant p53,” said Kaiser. “These findings are encouraging given the large number of cancer patients with p53 mutations that could benefit from such drugs.”
This study involved the application of an ensemble-based virtual screening approach, developed in the laboratory of Rommie Amaro, professor and endowed chair in the Department of Chemistry and Biochemistry at UC San Diego, which has the potential to identify compounds with increased cancer killing potential and with a broad spectrum of activity across a panel of p53 mutants. The researchers showed that their compounds bind mutant p53 and change mutant p53 conformation to wild type-like structures. This restores p53 DNA binding activity to activate the p53 transcriptional response, which in turn prevents tumor progression in mouse models selectively for tumors with a p53 missense mutation.
Challenges remain to define exact mechanisms and develop highly active corrector drugs for mutated p53 and future experiments are needed to optimize pharmacological properties to progress towards clinical therapeutics.
The study was supported by the National Institutes of Health and the Department of Defense.
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