Susan Wirtz

Developing a geolocated directory of PrEP-providing clinics: the PrEP Locator Protocol

Synthesis and Biological Evaluation of 2‘,3‘-Didehydro-2‘,3‘-dideoxy-5- fluorocytidine (D4FC) Analogues: Discovery of Carbocyclic Nucleoside Triphosphates with Potent Inhibitory Activity against HIV-1 Reverse Transcriptase

Journal of Medicinal Chemistry, Feb 20, 1999

The discovery of a novel cytosine nucleoside, â-D-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine ... more The discovery of a novel cytosine nucleoside, â-D-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine (D-D4FC), as a potent antihuman immunodeficiency virus (HIV) agent led us to synthesize a series of analogues and derivatives of â-D-D4FC that could be more selective and also possess increased glycosidic bond stability. The synthesized D-D4FC analogues were evaluated for antiHIV-1 activity, anticancer activity, and cytotoxicity in various cells. The biological data demonstrated that the 5-substitution of â-D-D4FC with bromine (6c) and iodine (6d) resulted in the loss of antiviral activity, and the R-D anomer (7a) of D-D4FC was also devoid of activity. The 5-fluorouracil analogues (6b and 7b) of D-D4FC were less potent and more cytotoxic than the parent compound, whereas the â-L-D4FU (11) showed both potent anti-HIV-1 activity and cytotoxicity. N4and 5′-O-acyl derivatives (17, 15a-c) of â-D-D4FC exhibited comparable antiviral activity to â-D-D4FC. In contrast, the N4-isopropyl derivative (20) of â-D-D4FC was not active against HIV-1, even at 100 μM. The carbocyclic analogues (26a,b) of D4FC demonstrated weak activity against HIV-1 and no toxicity in various cells. The triphosphates (27a,b) of the carbocyclic nucleosides demonstrated potent inhibitory activity against recombinant HIV-1 reverse transcriptase at submicromolar concentrations. Of the compounds tested as potential anticancer agents, â-D-, R-D-, and â-L-D4FU (6b, 7b, 11) showed inhibitory activity against rat glioma and modest activity against human lung carcinoma, lymphoblastoid, and skin melanoma cells.

Developing a Web-Based Geolocated Directory of HIV Pre-Exposure Prophylaxis-Providing Clinics: The PrEP Locator Protocol and Operating Procedures

JMIR public health and surveillance, Sep 6, 2017

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Users of a National Directory of PrEP Service Providers: Beliefs, Self-Efficacy, and Progress Toward Prescription

Journal of Acquired Immune Deficiency Syndromes, Aug 1, 2018

PrEP (HIV pre-exposure prophylaxis) is highly effective in preventing HIV transmission. In a meta... more PrEP (HIV pre-exposure prophylaxis) is highly effective in preventing HIV transmission. In a meta-analysis by Fonner et al., PrEP was shown to reduce the risk of HIV acquisition by 70% for adherent users in all risk groups including men who have sex with men, heterosexually active adults and people who inject drugs. An estimated 98,732 individuals had initiated PrEP regimens from 2012-2016, whereas 1,232,000 adults in the United States were estimated to be indicated for PrEP in 2016 alone. More research is needed on how to facilitate PrEP uptake along the HIV prevention care continuum. One previously identified barrier to care is locating a provider willing to prescribe PrEP. A tool recently developed by the authors, PrEP Locator, is an online national database of PrEPproviding clinics that provides information for the nearest clinics based on a user's location. The database of over 2100 clinics was originally developed from all available state health department directories, local health department directories, non-governmental organization directories, and HIV-related medical organization member surveys. It is routinely updated through a web form that allows clinics or the general public to suggest new clinics, with Emory staff vetting all clinics before inclusion in the database. Information provided to website visitors includes clinic contact information, a link-out for map-based directions to each clinic, and clinic search filters for individuals to identify services that assist with manufacturer copay programs or provide care for those without health insurance. To explore user behavior before and after accessing PrEP Locator, from June-July 2017 we recruited users to complete baseline and one-month follow-up surveys. The recruitment ad showed immediately when users landed at PrEPLocator.org. Individuals using the website for personal use and over 18 years of age were eligible to take the survey. The survey collected data on demographics, 9 PrEP eligibility, 10 PrEP awareness, 11 PrEP knowledge,

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Mololipids, A New Series of Anti-HIV Bromotyramine-Derived Compounds from a Sponge of the Order Verongida

Journal of Natural Products, Apr 1, 2000

A new series of lipids called mololipids have been identified from an Hawaiian sponge of the orde... more A new series of lipids called mololipids have been identified from an Hawaiian sponge of the order Verongida. The structures of these lipids was deduced from spectroscopic data of the lipid mixture combined with GC-MS analysis. The core of this novel series of lipids is a bromotyramine homoserine-derived moiety known as moloka&#39;iamine (1) which is found in many Verongid sponge metabolites. Moloka&#39;iamine forms bisamides with a diverse series of fatty acids and the mololipids mixture (2) was active against HIV-1 with an EC(50) of 52.2 microM without cytotoxicity in human lymphocytes (IC(50) &gt; 100 microM).

Developing a Web-Based Geolocated Directory of HIV Pre-Exposure Prophylaxis-Providing Clinics: The PrEP Locator Protocol and Operating Procedures

JMIR Public Health and Surveillance, 2017

Background: Human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP) is highly effectiv... more Background: Human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP) is highly effective in preventing HIV transmission, yet patients interested in learning more about PrEP or in getting a PrEP prescription may not be able to find local medical providers willing to prescribe PrEP. We sought to create a national database of PrEP-providing clinics to allow for patients to have access to a unified, vetted source of PrEP providers in an easily accessible database. To develop the protocol and operating procedures for the PrEP Locator, we conducted a series of 7 key informant interviews with experts who had organized PrEP or other HIV service directories. We convened an external advisory committee and a collaborators board to gain expert and community-situated perspectives. Results: At its public release in September 2016, the database included 1,272 PrEP-providing clinics, including clinics in all 50 states and in Puerto Rico. Web searches, referrals, and outreach to state health departments identified 58 unique lists of PrEP-providing clinics, with 33 from state health departments, 6 from government localities, 2 from professional medical organizations, and 19 from nongovernmental organizations. Out of the 2,420 clinics identified from the lists and Web searches, we removed 798 as duplicate entries, and we determined that 350 were ineligible for listing. The most common reasons for ineligibility were not having the appropriate medical licensure to prescribe PrEP (67/350) or not prescribing PrEP, based on self-report (192/350). Key informant interviews shaped important protocol decisions, such as listing clinics instead of individual clinicians as the primary data element and streamlining data collection to facilitate scalability. We developed a Web interface to provide public access to the data, with geolocated data display, search filter functionality, a webform for public suggestions of new clinics, and a publicly available directory Web tool that can be embedded in websites. In the 6 months following release, preplocator.org and hosting websites had received over 35,000 unique views and 300 clinic additions, and 5 websites had initiated hosting of the widget. Conclusions: Directories exist for many preventive and treatment services. As new medical applications become available, there will be a corresponding need to develop new directories for service provision. Geolocated directories can assist patients in accessing care and have the potential to increase demand for and access to newer, more efficacious medical interventions. Early choices in the development of service directories have long-lasting impact, because once data collection begins, it can be challenging to reverse course. The PrEP Locator protocol may inform early decisions in the development of future service directories. Additionally, the case study on developing the PrEP Locator demonstrates the importance of formative work in identifying service-specific factors that can guide decisions on directory development.

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Developing a geolocated directory of PrEP-providing clinics: the PrEP Locator Protocol

Cohort Profile: The HIV Atlanta Veterans Affairs Cohort Study (HAVACS)

International Journal of Epidemiology, 2016

HAVACS (HIV Atlanta VA Cohort Study) was initiated as an open cohort in 1982 to enhance clinical ... more HAVACS (HIV Atlanta VA Cohort Study) was initiated as an open cohort in 1982 to enhance clinical care and research for all HIV-positive veterans seeking care at the Atlanta Veterans Affairs Medical Center. The HAVACS database provides health care providers with a summary of patient information, while also being used for surveillance and research analyses. Moreover, it has been used to assess the feasibility of new studies, and aids in the identification of patients eligible for approved research protocols. Essentially, it serves as an ongoing prospective, observational study for interdisciplinary HIV research in clinical, basic, epidemiological, biostatistical and social sciences. Today, HAVACS is a powerful database utilized for the investigation of HIV-positive patients with respect to HIV and ageing, non AIDS-related malignancies, hepatitis B and C co-infections, novel immunological markers for inflammation, and highly-active antiretroviral therapy (HAART) start time and drug sequencing. HAVACS has no independent funding; maintenance of data and reports are supported by a combination of research coordinators and clinicians.

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Hiv-Infected Treatment-Naïve Individuals Have Low Circulating Progenitor Cells

Journal of the American College of Cardiology, 2013

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Manadomanzamines A and B: A Novel Alkaloid Ring System with Potent Activity against Mycobacteria and HIV-1

Journal of the American Chemical Society, 2003

Two novel alkaloids, named manadomanzamines A (1) and B (2), were isolated from an Indonesian spo... more Two novel alkaloids, named manadomanzamines A (1) and B (2), were isolated from an Indonesian sponge Acanthostrongylophora sp. (Haplosclerida: Petrosiidae). Their structures were elucidated and shown to be a novel organic skeleton related to the manzamine type alkaloids. Their absolute configuration and conformation were determined by CD, NOESY, and molecular modeling analysis. The microbial community analysis for the sponge that produces these unprecedented alkaloids has also been completed. Manadomanzamines A (1) and B (2) exhibited strong activity against Mycobacterium tuberculosis (Mtb) with MIC values of 1.9 and 1.5 µg/mL, respectively. Manadomanzamines A and B also exhibit activities against human immunodeficiency virus (HIV-1) and AIDS opportunistic fungal infections.

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Mololipids, A New Series of Anti-HIV Bromotyramine-Derived Compounds from a Sponge of the Order Verongida

Journal of Natural Products, 2000

A new series of lipids called mololipids have been identified from an Hawaiian sponge of the orde... more A new series of lipids called mololipids have been identified from an Hawaiian sponge of the order Verongida. The structures of these lipids was deduced from spectroscopic data of the lipid mixture combined with GC-MS analysis. The core of this novel series of lipids is a bromotyramine homoserine-derived moiety known as moloka&#39;iamine (1) which is found in many Verongid sponge metabolites. Moloka&#39;iamine forms bisamides with a diverse series of fatty acids and the mololipids mixture (2) was active against HIV-1 with an EC(50) of 52.2 microM without cytotoxicity in human lymphocytes (IC(50) &gt; 100 microM).

Synthesis and Anti-HIV and Anti-HBV Activities of 2‘-Fluoro-2‘,3‘-unsaturated l-Nucleosides

Journal of Medicinal Chemistry, 1999

The synthesis of L-nucleoside analogues containing 2′-vinylic fluoride was accomplished by direct... more The synthesis of L-nucleoside analogues containing 2′-vinylic fluoride was accomplished by direct condensation method, and their anti-HIV and anti-HBV activities were evaluated in vitro. The key intermediate 8, the sugar moiety of our target compounds, was prepared from 1,2-Oisopropylidene-L-glyceraldehyde via (R)-2-fluorobutenolide intermediate 5 in five steps. Coupling of the acetate 8 with the appropriate heterocycles (silylated uracil, thymine, N 4 -benzoylcytosine, N 4 -benzoyl-5-fluorocytosine, 6-chloropurine, and 6-chloro-2-fluoropurine) in the presence of Lewis acid afforded a series of 2′-fluorinated L-nucleoside analogues (15-18, 23-26, 36-45). The newly synthesized compounds were evaluated for their antiviral activities against HIV-1 in human peripheral blood mononuclear (PBM) cells and HBV in 2.2.15 cells. Cytosine 23, 5-fluorocytosine 25, and adenine 36 derivatives exhibited moderate to potent anti-HIV (EC 50 0.51, 0.17, and 1.5 µM, respectively) and anti-HBV (EC 50 0.18, 0.225, and 1.7 µM, respectively) activities without significant cytotoxicity up to 100 µM in human PBM, Vero, CEM, and HepG2 cells.

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Synthesis and Biological Evaluation of 2‘,3‘-Didehydro-2‘,3‘-dideoxy-5- fluorocytidine (D4FC) Analogues: Discovery of Carbocyclic Nucleoside Triphosphates with Potent Inhibitory Activity against HIV-1 Reverse Transcriptase

Journal of Medicinal Chemistry, 1999

The discovery of a novel cytosine nucleoside, â-D-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine ... more The discovery of a novel cytosine nucleoside, â-D-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine (D-D4FC), as a potent antihuman immunodeficiency virus (HIV) agent led us to synthesize a series of analogues and derivatives of â-D-D4FC that could be more selective and also possess increased glycosidic bond stability. The synthesized D-D4FC analogues were evaluated for antiHIV-1 activity, anticancer activity, and cytotoxicity in various cells. The biological data demonstrated that the 5-substitution of â-D-D4FC with bromine (6c) and iodine (6d) resulted in the loss of antiviral activity, and the R-D anomer (7a) of D-D4FC was also devoid of activity. The 5-fluorouracil analogues (6b and 7b) of D-D4FC were less potent and more cytotoxic than the parent compound, whereas the â-L-D4FU (11) showed both potent anti-HIV-1 activity and cytotoxicity. N4and 5′-O-acyl derivatives (17, 15a-c) of â-D-D4FC exhibited comparable antiviral activity to â-D-D4FC. In contrast, the N4-isopropyl derivative (20) of â-D-D4FC was not active against HIV-1, even at 100 μM. The carbocyclic analogues (26a,b) of D4FC demonstrated weak activity against HIV-1 and no toxicity in various cells. The triphosphates (27a,b) of the carbocyclic nucleosides demonstrated potent inhibitory activity against recombinant HIV-1 reverse transcriptase at submicromolar concentrations. Of the compounds tested as potential anticancer agents, â-D-, R-D-, and â-L-D4FU (6b, 7b, 11) showed inhibitory activity against rat glioma and modest activity against human lung carcinoma, lymphoblastoid, and skin melanoma cells.

Modification at the C9 position of the marine natural product isoaaptamine and the impact on HIV-1, mycobacterial, and tumor cell activity

Bioorganic & Medicinal Chemistry, 2006

As part of an investigation to generate optimized drug leads from marine natural pharmacophores f... more As part of an investigation to generate optimized drug leads from marine natural pharmacophores for the treatment of neoplastic and infectious diseases, a series of novel isoaaptamine analogs were prepared by coupling acyl halides to the C9 position of isoaaptamine (2) isolated from the Aaptos sponge. This library of new semisynthetic products was evaluated for biological activity against HIV-1, Mtb, AIDS-OI, tropical parasitic diseases, and cancer. Compound 4 showed potent activity against HIV-1 (EC 50 0.47 μg/mL), compound 19 proved to possess remarkable activity against Mycobacterium intracellulare with an IC 50 and MIC value of 0.15 and 0.31 μg/mL, while compounds 4 and 17 possessed anti-leishmanial activity with IC 50 values of 0.1 and 0.4 μg/mL, respectively. Compounds 16 and 17 showed antimalarial activity with EC 50 values of 230 and 240 ng/mL, respectively, and compound 14 exhibited an EC 50 of 0.05 μM against the Leukemia cell line K-562.

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In Vitro Selection and Analysis of Human Immunodeficiency Virus Type 1 Resistant to Derivatives of β-2′,3′-Didehydro-2′,3′-Dideoxy-5-Fluorocytidine

Antimicrobial Agents and Chemotherapy, 2005

Serial passage of human immunodeficiency virus type 1 in MT-2 cells in increasing concentrations ... more Serial passage of human immunodeficiency virus type 1 in MT-2 cells in increasing concentrations of the d - and l -enantiomers of β-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine (d4FC) resulted in the selection of viral variants with reverse transcriptase substitutions M184I or M184V for l -d4FC and I63L, K65R, K70N, K70E, or R172K for d -d4FC. Phenotypic analysis of site-directed mutants defined the role of these mutations in reducing susceptibility to l - or d -d4FC.

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Users of a National Directory of PrEP Service Providers: Beliefs, Self-Efficacy, and Progress Toward Prescription

JAIDS Journal of Acquired Immune Deficiency Syndromes, 2018

PrEP (HIV pre-exposure prophylaxis) is highly effective in preventing HIV transmission. In a meta... more PrEP (HIV pre-exposure prophylaxis) is highly effective in preventing HIV transmission. In a meta-analysis by Fonner et al., PrEP was shown to reduce the risk of HIV acquisition by 70% for adherent users in all risk groups including men who have sex with men, heterosexually active adults and people who inject drugs. An estimated 98,732 individuals had initiated PrEP regimens from 2012-2016, whereas 1,232,000 adults in the United States were estimated to be indicated for PrEP in 2016 alone. More research is needed on how to facilitate PrEP uptake along the HIV prevention care continuum. One previously identified barrier to care is locating a provider willing to prescribe PrEP. A tool recently developed by the authors, PrEP Locator, is an online national database of PrEPproviding clinics that provides information for the nearest clinics based on a user's location. The database of over 2100 clinics was originally developed from all available state health department directories, local health department directories, non-governmental organization directories, and HIV-related medical organization member surveys. It is routinely updated through a web form that allows clinics or the general public to suggest new clinics, with Emory staff vetting all clinics before inclusion in the database. Information provided to website visitors includes clinic contact information, a link-out for map-based directions to each clinic, and clinic search filters for individuals to identify services that assist with manufacturer copay programs or provide care for those without health insurance. To explore user behavior before and after accessing PrEP Locator, from June-July 2017 we recruited users to complete baseline and one-month follow-up surveys. The recruitment ad showed immediately when users landed at PrEPLocator.org. Individuals using the website for personal use and over 18 years of age were eligible to take the survey. The survey collected data on demographics, 9 PrEP eligibility, 10 PrEP awareness, 11 PrEP knowledge,

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