The short-term effects of COVID-19 on HIV and AIDS control efforts among female sex workers in Indonesia.

BACKGROUND: The COVID-19 pandemic has raised concerns as to its impact on other health programs. One program that appears particularly vulnerable is HIV and AIDS. We undertook an assessment of COVID-19 impact on HIV control efforts in Indonesia for a sub-population that has received little attention in the global literature-female sex workers (FSW). METHODS: The study was undertaken in 23 National AIDS program priority districts. Four sources of monthly data during January-July 2020 were considered. COVID-19 infection data were extracted from national and district surveillance systems. Combination prevention program outputs were reported by civil society organizations (CSOs) providing community support services to FSW. These organizations also undertook monthly scans of levels of commercial sex activity and HIV testing availability. We also considered data from an ongoing HIV community screening trial. The primary mode of analysis entailed comparisons of levels and trends of indicators from the four data series. RESULTS: Commercial sex activity was severely curtailed in April-May in many districts. While recovering to pre-COVID-19 levels in "Localization" areas, the number of active FSW in July was one-third below that in February. HIV testing service availability declined by 50% at health facilities before recovering slowly, while mobile clinic services largely ceased during April-June. Numbers of FSW reached, condoms distributed, FSW tested for HIV, HIV cases detected, and FSW starting treatment all declined precipitously in April/May but had largely recovered to pre-COVID-19 levels by July. We found only a temporary dip in treatment initiation rates among HIV positive FSW and no discernible impact on treatment retention. The HIV community screening trial data revealed significant demand for HIV testing among FSW that was not being met even before the onset of COVID-19. CONCLUSIONS: COVID-19 has had at least short-run economic effects on FSW and the national response to HIV and AIDS targeting FSW. However, the effects appear to have been cushioned by community-based services and support in study districts. The findings make a compelling case for the expansion of community-based services irrespective of the future trajectory of COVID-19. As COVID-19 has not yet been contained, the trajectory of economic activity and service delivery is uncertain.

Web-Based Multifaceted Approach for Community-Based HIV Self-Testing Among Female Sex Workers in Indonesia: Protocol for a Randomized Community Trial.

BACKGROUND: New HIV infections in Indonesia continue to be concentrated among key populations, including female sex workers (FSWs). However, increasing HIV testing among this subpopulation remains a challenge, necessitating exploration into alternative testing modalities. OBJECTIVE: This study aims to assess whether the addition of an oral fluid testing option in community settings would increase the rate of HIV case identification among FSWs. Because the study was implemented early in the outbreak of COVID-19 in Indonesia, a secondary objective is to assess approaches and tools for implementing both community outreach and community HIV screening for FSWs during pandemic conditions. METHODS: We undertook a community-based randomized trial in 23 national priority districts in which community outreach services were being provided. Community-based screening using an oral fluid-based rapid test was added to the community outreach standard of care in intervention districts with clients having the option of performing the test themselves or being assisted by outreach workers. A web-based system was created to screen for eligibility and collect participant data and test results, facilitating the process for both unassisted and assisted participants. Participants with reactive screening results were encouraged to undergo HIV testing at a health facility to confirm their diagnosis and initiate antiretroviral treatment as needed. Multiple means of recruitment were deployed including through outreach workers and social media campaigns. RESULTS: Of the 1907 FSWs who registered, met the eligibility criteria, and gave consent to participate, 1545 undertook community oral fluid test (OFT) screening. Most (1516/1545, 98.1%) opted for assisted screening. Recruitment via social media fell far short of expectations as many who registered independently for the OFT because of the social media campaign did not identify as FSWs. They were eventually not eligible to participate, but their interest points to the possibility of implementing HIV self-testing in the general population. The successful recruitment through outreach workers, facilitated by social media, indicates that their roles remain crucial in accessing FSW networks and improving HIV testing uptake. CONCLUSIONS: The addition of HIV self-testing to the standard of care supported by a web-based data collection system was able to increase HIV case identification among FSWs in intervention districts. The high satisfaction of OFT users and the interest of the general population toward this alternative testing modality are promising for scaling up community HIV screening nationally. TRIAL REGISTRATION: ClinicalTrials.gov NCT04578145; https://clinicaltrials.gov/ct2/show/NCT04578145. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/27168.

Exploiting the Protein Corona from Cell Lysate on DNA Functionalized Gold Nanoparticles for Enhanced mRNA Translation.

This study describes the use of DNA functionalized gold nanoparticles (AuNPs) to enhance the synthesis of proteins in cell lysate and examines the mechanisms behind the enhanced mRNA translation. With an appropriate DNA oligomer sequence that hybridizes to the 3'-untranslated region of two mRNA of interest, insulin and green fluorescent protein (GFP), we found that these DNA conjugated AuNPs (AuNP-DNA) introduced into HeLa cell lysate enhanced the synthesis of insulin and GFP by up to 2.18 and 1.80-fold, respectively, over baseline production with just the mRNA present. The insulin synthesis was markedly reduced with non-DNA citrate-capped AuNP (1.25-fold) and AuNP-DNA with a nonspecific poly(T) sequence (1.25-fold). We showed that both nonspecific adsorption of ribosomes and translation factors to form a lysate protein corona on AuNP-DNA and weak hybridization between DNA oligomers and mRNA of interest were important factors that brought translation factors, ribosomes, and mRNA into close proximity of each other. This could reduce the recycling time of ribosomes during mRNA translation, thereby increasing the efficiency of protein synthesis. The outcome of this work shows that with rational DNA design, it could be possible to modulate intracellular biological processes with AuNP-DNA and increase their production of proteins for various biomedical applications.

Silver-Catalyzed 1,3-Acyloxy Migration/Diels-Alder Reaction of 1,9-Dien-4-yne Esters to Partially Hydrogenated Isoquinolines.

A synthetic method to prepare partially hydrogenated isoquinolines efficiently from silver-mediated [3,3]-sigmatropic rearrangement/Diels-Alder reaction of 1,9-dien-4-yne esters is described. The reactions were shown to be robust with a wide variety of substitution patterns tolerated to provide the corresponding nitrogen-containing heterocyclic products in good to excellent yields. This includes examples containing a bridgehead sp3 quaternary carbon center as well as the cycloisomerization of one substrate to give the corresponding bicyclic adduct in excellent yield at the gram scale.

Gold-Catalyzed Cycloisomerization and Diels-Alder Reaction of 1,4,9-Dienyne Esters to 3 a,6-Methanoisoindole Esters with Pro-Inflammatory Cytokine Antagonist Activity.

A synthetic method to prepare 3a,6-methanoisoindole esters efficiently by gold(I)-catalyzed tandem 1,2-acyloxy migration/Nazarov cyclization followed by Diels-Alder reaction of 1,4,9-dienyne esters is described. We also report the ability of one example to inhibit binding of tumor necrosis factor-α (TNF-α) to the tumor necrosis factor receptor 1 (TNFR1) site and TNF-α-induced nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) activation in cell at a half-maximal inhibitory concentration (IC50 ) value of 6.6 µM. Along with this is a study showing the isoindolyl derivative to exhibit low toxicity toward human hepatocellular liver carcinoma (HepG2) cells and its possible mode of activity based on molecular modeling analysis.

Ligand-controlled product selectivity in gold-catalyzed double cycloisomerization of 1,11-dien-3,9-diyne benzoates.

A synthetic method to prepare tricyclic bridged heptenones and hexenones from gold(I)-catalyzed double cycloisomerization of 1,11-dien-3,9-diyne benzoates is described. A divergence in product selectivity was achieved by fine-tuning the steric nature of the ligand of the Au(I) catalyst. In the presence of [MeCNAu(JohnPhos)](+)SbF6(-) (JohnPhos = (1,1'-biphenyl-2-yl)-di-tert-butylphosphine) as the catalyst, tandem 1,3-acyloxy migration/metallo-Nazarov cyclization/1,6-enyne addition/Cope rearrangement of the substrate was found to selectively occur to afford the bridged heptenone adduct. In contrast, changing the Au(I) catalyst to [MeCNAu(Me4tBuXPhos)](+)SbF6(-) (Me4tBuXPhos = di-tert-butyl(2',4',6'-triisopropyl-3,4,5,6-tetramethyl-[1,1'-biphenyl]-2-yl)phosphine) was observed to result in the 1,11-dien-3,9-diyne benzoate undergoing a more rapid tandem 1,3-acyloxy migration/metallo-Nazarov cyclization/[4 + 2]-cyclization pathway to give the bridged hexenone derivative.

Discovery of a small-molecule inhibitor of STAT3 by ligand-based pharmacophore screening.

STAT3 modulates the transcription of a wide variety of regulatory genes involved in cell proliferation, differentiation, migration, apoptosis, and other critical cellular functions. Constitutive activation of STAT3 has been detected in a wide spectrum of human malignancies. A pharmacophore model constructed from a training set of STAT3 inhibitors binding to the SH2 domain was used to screen an in-house database of compounds, from which azepine 1 emerged as a top candidate. Compound 1 inhibited STAT3 DNA-binding activity in vitro and attenuated STAT3-directed transcription in cellulo with comparable potency to the well-known STAT3 inhibitor S3I-201. A fluorescence polarization assay revealed that compound 1 targeted the SH2 domain of STAT3. Furthermore, compound 1 inhibited STAT3 phosphorylation in cells without affecting the total expression of STAT3. This study also validates the use of pharmacophore modeling to identify inhibitors of protein-protein interactions.

Pharmacophore modeling for the identification of small-molecule inhibitors of TACE.

Tumor necrosis factor α-converting enzyme (TACE) plays a critical role in diverse physiological processes such as inflammation, hematopoiesis, and development. In this study, a pharmacophore model constructed from a training set of TACE inhibitors was used to screen an in-house database of organic compounds, from which compound 1 emerged as a top candidate. In a cell-free assay, compound 1 inhibited TACE enzymatic activity in a dose-dependent manner. Moreover, compound 1 inhibited the production of soluble TNF-α in human acute monocytic leukemia THP-1 cells without impacting nitric oxide production, and exhibited anti-proliferative activity against THP-1 cells. We envisage that compound 1 may be employed as a useful scaffold for the development of more potent TACE inhibitors. This study also validates the use of pharmacophore modeling to identify enzyme inhibitors.

Silver acetate catalyzed hydroamination of 1-(2-(sulfonylamino)phenyl)prop-2-yn-1-ols to (Z)-2-methylene-1-sulfonylindolin-3-ols.

A method to prepare (Z)-2-methylene-1-sulfonylindolin-3-ols efficiently that relies on silver acetate catalyzed hydroamination of 1-(2-(sulfonylamino)phenyl)prop-2-yn-1-ols is reported. The reactions proceed rapidly at room temperature with catalyst loadings as low as 1 mol % under conditions that did not require the exclusion of air or moisture. The utility of this N-heterocyclic ring-forming strategy as a synthetic tool that makes use of unsaturated alcohols was exemplified by the conversion of the (Z)-2-methylene-1-sulfonylindolin-3-ol to examples of other members of the indole family of compounds.

Gold-catalyzed tandem 1,3-migration/[2 + 2] cycloaddition of 1,7-enyne benzoates to azabicyclo[4.2.0]oct-5-enes.

A synthetic method that relies on gold(I)-catalyzed tandem 1,3-migration/[2 + 2] cycloaddition of 1,7-enyne benzoates to prepare azabicyclo[4.2.0]oct-5-enes is described.

Cyclopropyl carbinol rearrangement for benzo-fused nitrogen ring synthesis.

A synthetic method that relies on gold-catalysed cyclopropyl carbinol rearrangement of 2-tosylaminophenyl cyclopropylmethanols to prepare 2,3-dihydro-1H-benzo[b]azepines and 2-vinylindolines efficiently is reported. The reactions were shown to be chemoselective, with secondary and tertiary alcohol substrates exclusively providing benzo-fused five- and seven-membered ring products, respectively. The ring-forming process was also found to proceed in moderate to excellent yields under mild conditions only in the presence of the gold and silver catalyst combination. The mechanism is thought to involve activation of the alcohol by the (p-CF(3)C(6)H(4))(3)PAuCl/AgOTf (Tf = triflate) catalyst, resulting in ionization of the starting material. The tertiary carbocationic intermediate generated in situ in this manner then triggers ring-opening of the cyclopropane moiety and trapping by the tethered aniline group to give the 2,3-dihydro-1H-benzo[b]azepine. Cyclopropane ring fragmentation of the secondary carbocationic analogue, on the other hand, results in diene formation followed by subsequent intramolecular hydroamination to afford the 2-vinylindoline.