Daria Hazuda

Last updated
Daria Hazuda
Alma mater Rutgers University, State University of New York at Stony Brook
Known fordeveloping first approved HIV integrase inhibitor
Scientific career
Fields Biology, Biochemistry
Institutions Merck

Daria J Hazuda is a biochemist known for discovering the first HIV Integrase Strand Transfer Inhibitors (InSTIs) and leading the development of the first HIV integrase inhibitor to gain FDA approval, Isentress (raltegravir). [1] Her lab also determined these inhibitors' mechanism of action and ways the virus could develop resistance to them. [1] Hazuda has also performed extensive research and led the development of antivirals for Hepatitis C Virus (HCV) including Elbasvir and Grazoprevir. [2] She currently serves as Vice President for Infectious Diseases Discovery for Merck and Chief Scientific Officer of their MRL Cambridge Exploratory Science Center. [3]

Contents

Early life and education

Hazuda was raised in Hillsborough Township, New Jersey. [4] Her father was an engineer and her mother worked in the regulatory-compliance division of Janssen Pharmaceutica (now a part of Johnson & Johnson). [4] She graduated in 1977 as the salutatorian at Hillsborough High School. [5] She initially pursued a premedical degree at Georgetown University, but fell in love with research during a part-time job in a lab and decided to go into drug discovery. [4] She earned got a B.S. from Rutgers University, followed by a PhD in biochemistry from the State University of New York at Stony Brook, where she trained with Cheng-Wen Wu. [2] She then did a post-doctoral research fellowship at Smith, Kline, and French in the department of Molecular Genetics. [2]

Career and research

Hazuda joined Merck in 1989, where she started as a Senior Research Biochemist in the antiviral research group. [1] She was initially assigned to work on influenza, but she asked to be switched to HIV research. [6] She continues to oversee Merck's HIV research, which includes the development of long-acting antiretrovirals. [7] She has also been instrumental in the development of antiviral treatments for Hepatitis C Virus (HCV), leading the development of antivirals for Hepatitis C Virus (HCV) including Elbasvir and Grazoprevir. [1] Additionally, as Chief Scientific Officer of the Merck Research Laboratory Cambridge Exploratory Science Center she oversees research on interactions between the human microbiome and immunity. [7] She previously served as Global Director of Scientific Affairs for Antivirals in Merck's division of Global Human Health, as well as co-site head of basic research for the Merck West Point research facility. [1]

Hazuda is on the editorial board of the American Chemical Society Journal on Anti-infectives Research and the Journal of Viral Eradication. [1] She previously served on the scientific advisory boards of and the Center for Aids Research (CFAR) of UCLA and the Gladstone Institute as well as the NIH Aids Research Advisory Committee (ARAC). [1] She is a member of The Forum for HCV Collaborative Research, the NCI Basic Sciences Board of Scientific Counselors, and the Scientific Program Advisory Council of the American Foundation for Aids Research (AMFAR). [1]

Research on HIV-1 integrase inhibitors

As a retrovirus, HIV has an RNA genome which it reverse transcribes into a double-stranded DNA copy, which it then inserts into the host cell's genome. This insertion is done by an enzyme called integrase which has several sequential functions: it binds to the ends of the viral DNA and processes them by removing a couple of nucleotides from each end. It then aids the 3'OH of the viral DNA in attacking the phosphodiester backbone of the host DNA, cleaving it at an integration site and attaching the viral DNA in a step called strand transfer. Cellular enzymes then fill in the gaps. [8]

Hazuda was not the first or only scientist working to develop integrase inhibitors. [6] However, whereas most scientists were focused on blocking the early steps (and were not having much success), Hazuda focused on the later, strand transfer, step. In order to screen for inhibitors of this step, she had to develop a new assay, which involved viral "donor DNA" mimics attached to the wells of a plate and labeled target DNA. Integrase strand transfer activity was measured by the labeled DNA getting stuck to the well after unreacted products were washed off. The assay worked, but it was incompatible with the available robots, so she and two assistants, over several months in 1999, had to pipet over 250,000 compounds by hand. [9]

In 2000, her group published two key papers showing effective integrase inhibitors could be made. [6] She demonstrated that the inhibitors she had identified acted as Integrase Strand Transfer Inhibitor (InSTI), binding to viral DNA-bound integrase, chelating the active site magnesium ions, and thereby preventing the complex from binding to cellular DNA. [10] [11] Through a collaboration with Merck researchers in Rome, raltegravir (Isentress) was found - it was originally developed as a potential hepatitis C polymerase inhibitor which was found to be ineffective for that purpose. [6] It was approved by the FDA for use in patients with HIV in October 2007. [6]

Honors and awards

Hazuda has received the Bernie Field Lecture Award and the David Barry DART (Development of Antiretroviral Therapies) Achievement Award. [1] The integrase inhibitor she led the development of, Isentress (raltegravir), was awarded the Prix Galien prize in 2008. [1] She was awarded the Italian Premio Galeno Award for this work. [2] In 2019 she Ohio State University presented her with the Distinguished Research Career Award. [2] In 2017, she was part of a team of chemists awarded the “Heroes of Chemistry” award from the American Chemical Society for the development of the HCV combination therapy Elbasvir/Grazoprevir. [12] She was Elected as a Fellow to the American Academy of Microbiology in 2010. [2]

Key papers

Related Research Articles

<span class="mw-page-title-main">Integrase</span> Class of enzymes

Retroviral integrase (IN) is an enzyme produced by a retrovirus that integrates its genetic information into that of the host cell it infects. Retroviral INs are not to be confused with phage integrases (recombinases) used in biotechnology, such as λ phage integrase, as discussed in site-specific recombination.

<span class="mw-page-title-main">Zidovudine</span> Antiretroviral medication

Zidovudine (ZDV), also known as azidothymidine (AZT), is an antiretroviral medication used to prevent and treat HIV/AIDS. It is generally recommended for use in combination with other antiretrovirals. It may be used to prevent mother-to-child spread during birth or after a needlestick injury or other potential exposure. It is sold both by itself and together as lamivudine/zidovudine and abacavir/lamivudine/zidovudine. It can be used by mouth or by slow injection into a vein.

Reverse-transcriptase inhibitors (RTIs) are a class of antiretroviral drugs used to treat HIV infection or AIDS, and in some cases hepatitis B. RTIs inhibit activity of reverse transcriptase, a viral DNA polymerase that is required for replication of HIV and other retroviruses.

<span class="mw-page-title-main">Lamivudine</span> Chemical compound

Lamivudine, commonly called 3TC, is an antiretroviral medication used to prevent and treat HIV/AIDS. It is also used to treat chronic hepatitis B when other options are not possible. It is effective against both HIV-1 and HIV-2. It is typically used in combination with other antiretrovirals such as zidovudine, dolutegravir, and abacavir. Lamivudine may be included as part of post-exposure prevention in those who have been potentially exposed to HIV. Lamivudine is taken by mouth as a liquid or tablet.

<span class="mw-page-title-main">Nucleoside analogue</span> Biochemical compound

Nucleoside analogues are nucleosides which contain a nucleic acid analogue and a sugar. Nucleotide analogs are nucleotides which contain a nucleic acid analogue, a sugar, and a phosphate group with one to three phosphates.

Human Immunodeficiency Virus (HIV) and Hepatitis C Virus (HCV) co-infection is a multi-faceted, chronic condition that significantly impacts public health. According to the World Health Organization (WHO), 2 to 15% of those infected with HIV are also affected by HCV, increasing their risk of morbidity and mortality due to accelerated liver disease. The burden of co-infection is especially high in certain high-risk groups, such as intravenous drug users and men who have sex with men. These individuals who are HIV-positive are commonly co-infected with HCV due to shared routes of transmission including, but not limited to, exposure to HIV-positive blood, sexual intercourse, and passage of the Hepatitis C virus from mother to infant during childbirth.

Entry inhibitors, also known as fusion inhibitors, are a class of antiviral drugs that prevent a virus from entering a cell, for example, by blocking a receptor. Entry inhibitors are used to treat conditions such as HIV and hepatitis D.

<span class="mw-page-title-main">Raltegravir</span> Chemical compound

Raltegravir, sold under the brand name Isentress, is an antiretroviral medication used, together with other medication, to treat HIV/AIDS. It may also be used, as part of post exposure prophylaxis, to prevent HIV infection following potential exposure. It is taken by mouth.

Integrase inhibitors (INIs) are a class of antiretroviral drug designed to block the action of integrase, a viral enzyme that inserts the viral genome into the DNA of the host cell. Since integration is a vital step in retroviral replication, blocking it can halt further spread of the virus. Integrase inhibitors were initially developed for the treatment of HIV infection but have been applied to other retroviruses. The class of integrase inhibitors called integrase strand transfer inhibitors (INSTIs) are in established medical use. Other classes, such as integrase binding inhibitors (INBIs), are still experimental.

<span class="mw-page-title-main">Resistance mutation (virology)</span>

A resistance mutation is a mutation in a virus gene that allows the virus to become resistant to treatment with a particular antiviral drug. The term was first used in the management of HIV, the first virus in which genome sequencing was routinely used to look for drug resistance. At the time of infection, a virus will infect and begin to replicate within a preliminary cell. As subsequent cells are infected, random mutations will occur in the viral genome. When these mutations begin to accumulate, antiviral methods will kill the wild type strain, but will not be able to kill one or many mutated forms of the original virus. At this point a resistance mutation has occurred because the new strain of virus is now resistant to the antiviral treatment that would have killed the original virus. Resistance mutations are evident and widely studied in HIV due to its high rate of mutation and prevalence in the general population. Resistance mutation is now studied in bacteriology and parasitology.

<span class="mw-page-title-main">HIV integration</span>

AIDS is caused by the human immunodeficiency virus (HIV). Individuals with HIV have what is referred to as a "HIV infection". When infected semen, vaginal secretions, or blood come in contact with the mucous membranes or broken skin of an uninfected person, HIV may be transferred to the uninfected person, causing another infection. Additionally, HIV can also be passed from infected pregnant women to their uninfected baby during pregnancy and/or delivery, or via breastfeeding. As a result of HIV infection, a portion of these individuals will progress and go on to develop clinically significant AIDS.

<span class="mw-page-title-main">Boceprevir</span> Chemical compound

Boceprevir is a protease inhibitor used to treat hepatitis caused by hepatitis C virus (HCV) genotype 1. It binds to the HCV nonstructural protein 3 active site.

<span class="mw-page-title-main">MK-2048</span> Chemical compound

MK-2048 is the Merck & Co. designation for a molecule in its pre-clinical drug discovery that is an integrase inhibitor-class of agent intended to be used against HIV infection. It is a second generation integrase design thought to be superior to the first available integrase inhibitor, raltegravir, in that "MK-2048 has a dissociation half-life of 32 hours on wild-type integrase—more than four times that of raltegravir", and its dissociation half-life against the important HIV integrase mutant N155H was on the same order of magnitude as that of raltegravir against wild-type virus, leading the Merck presenter to suggest the possibility of "reduced susceptibility to resistance mutations" for the second generation drug. MK-2048 is being investigated for use as part of a pre-exposure prophylaxis (PrEP) approach to the treatment of HIV infection. At the time of these reports, there was no indication of the time by which "MK-2048, or related compounds, [would] be ready for clinical trials".

<span class="mw-page-title-main">Integrasone</span> Chemical compound

Integrasone is a polyketide natural product, isolated from an unknown fungus, that has been shown to inhibit the HIV-1 integrase enzyme.

The first human immunodeficiency virus (HIV) case was reported in the United States in the early 1980s. Many drugs have been discovered to treat the disease but mutations in the virus and resistance to the drugs make development difficult. Integrase is a viral enzyme that integrates retroviral DNA into the host cell genome. Integrase inhibitors are a new class of drugs used in the treatment of HIV. The first integrase inhibitor, raltegravir, was approved in 2007 and other drugs were in clinical trials in 2011.

<span class="mw-page-title-main">Grazoprevir</span> Drug approved for the treatment of hepatitis C

Grazoprevir is a drug approved for the treatment of hepatitis C. It was developed by Merck and completed Phase III trials, used in combination with the NS5A replication complex inhibitor elbasvir under the trade name Zepatier, either with or without ribavirin.

Bacteriophage Mu, also known as mu phage or mu bacteriophage, is a muvirus of the family Myoviridae which has been shown to cause genetic transposition. It is of particular importance as its discovery in Escherichia coli by Larry Taylor was among the first observations of insertion elements in a genome. This discovery opened up the world to an investigation of transposable elements and their effects on a wide variety of organisms. While Mu was specifically involved in several distinct areas of research, the wider implications of transposition and insertion transformed the entire field of genetics.

Elbasvir/grazoprevir, sold under the brand name Zepatier, is a fixed-dose combination for the treatment of hepatitis C, containing elbasvir and grazoprevir. It is used to treat chronic hepatitis C virus (HCV) genotypes 1 or 4 infection in both treatment-naïve and treatment-experienced patients.

Bictegravir/emtricitabine/tenofovir alafenamide, sold under the brand name Biktarvy, is a fixed-dose combination antiretroviral medication for the treatment of HIV/AIDS. One tablet, taken orally once daily, contains 50 mg bictegravir, 200 mg emtricitabine, and 25 mg tenofovir alafenamide. It was approved for use in the United States in February 2018, and for use in the European Union in June 2018.

<span class="mw-page-title-main">Riccardo Cortese</span> Italian scientist and entrepreneur

Riccardo Cortese was an Italian scientist, entrepreneur, and innovator in the field of gene expression, drug discovery and genetic vaccines. His work led to the development of novel therapeutic strategies for the prevention and cure of viral infections, including HIV, HCV, Ebola and RSV. He pioneered a novel platform technology based on simian adenoviral vectors for prophylactic and therapeutic vaccines, and authored more than 300 publications in peer reviewed journals in the field of gene expression, transcriptional control, molecular virology and immunology.

References

  1. 1 2 3 4 5 6 7 8 9 10 "Daria Hazuda, PhD". Virology Education. Retrieved 2020-08-01.
  2. 1 2 3 4 5 6 "2018 Distinguished Research Career Award | College of Veterinary Medicine". vet.osu.edu. Retrieved 2020-08-01.
  3. ↑ "Meet Daria Hazuda, PhD". merck.com. Retrieved 2020-08-01.
  4. 1 2 3 Services, Star-Ledger Wire (2009-11-07). "N.J. native's research lead to Merck's groundbreaking HIV drug". nj. Retrieved 2020-08-01.
  5. ↑ "Spirit the key to goals, Hillsborough grads told", The Home News , June 17, 1977. Accessed May 4, 2022, via Newspapers.com. "Class salutatorian Daria J. Hazuda used her address to caution the community against allowing overcrowding expected at the school next year to result in any subsequent lowering of academic standards at the school."
  6. 1 2 3 4 5 Herper, Matthew. "Merck's AIDS Triumph". Forbes. Retrieved 2020-08-01.
  7. 1 2 Mullard, Asher (2019-05-31). "Daria Hazuda". Nature Reviews Drug Discovery. 18 (7): 492–493. doi: 10.1038/d41573-019-00091-y . PMID   31267069. S2CID   195773864.
  8. ↑ Craigie, Robert (2012). "The molecular biology of HIV integrase". Future Virology. 7 (7): 679–686. doi:10.2217/FVL.12.56. ISSN   1746-0794. PMC   3458710 . PMID   23024700.
  9. ↑ "Merck's New Integrase Inhibitor Isentress & Daria Hazuda: The long path to developing an AIDS drug". www.natap.org. Archived from the original on 2017-01-31. Retrieved 2020-08-01.
  10. ↑ Espeseth, Amy S.; Felock, Peter; Wolfe, Abigail; Witmer, Marc; Grobler, Jay; Anthony, Neville; Egbertson, Melissa; Melamed, Jeffrey Y.; Young, Steve; Hamill, Terence; Cole, James L. (2000-10-10). "HIV-1 integrase inhibitors that compete with the target DNA substrate define a unique strand transfer conformation for integrase". Proceedings of the National Academy of Sciences. 97 (21): 11244–11249. Bibcode:2000PNAS...9711244E. doi: 10.1073/pnas.200139397 . ISSN   0027-8424. PMC   17185 . PMID   11016953.
  11. ↑ Grobler, Jay A.; Stillmock, Kara; Hu, Binghua; Witmer, Marc; Felock, Peter; Espeseth, Amy S.; Wolfe, Abigail; Egbertson, Melissa; Bourgeois, Michele; Melamed, Jeffrey; Wai, John S. (2002-05-14). "Diketo acid inhibitor mechanism and HIV-1 integrase: Implications for metal binding in the active site of phosphotransferase enzymes". Proceedings of the National Academy of Sciences. 99 (10): 6661–6666. Bibcode:2002PNAS...99.6661G. doi: 10.1073/pnas.092056199 . ISSN   0027-8424. PMC   124459 . PMID   11997448.
  12. ↑ yinan. "Inside Perspectives on the Discovery of the Hep C Combo Therapy Elbasvir/Grazoprevir | WuXi XPress: for WuXi news and R&D insights" . Retrieved 2020-08-01.
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