Publications

To the Editor: (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC) is an acyclic nucleoside phosphonate analogue with broad-spectrum antiviral activity against DNA viruses, including herpesviruses (herpes simplex virus, varicella–zoster virus, cytomegalovirus, and Epstein–Barr virus), adenoviruses, poxviruses, and papillomaviruses.1,2 We recently showed that local injections of HPMPC into a life-threatening squamous papilloma of the hypopharynx–esophagus eradicated the tumor.2 Two years later, the patient was still free of disease. We report the use of HPMPC in three patients with AIDS and severe, relapsing anogenital human papillomavirus lesions. A 44-year-old homosexual man had been unsuccessfully treated for recurrent penile human papillomavirus lesions since December 1993 with curettage. © 1995, Massachusetts Medical Society. All rights reserved.

This study presents proof of concept for designing a novel HIV-1 covalent inhibitor targeting the highly conserved Tyr318 in the HIV-1 non-nucleoside reverse transcriptase inhibitors binding pocket to improve the drug resistance profiles. The target inhibitor <b>ZA-2</b> with a fluorosulfate warhead in the structure was found to be a potent inhibitor (EC₅₀ = 11-246 nM) against HIV-1 IIIB and a panel of NNRTIs-resistant strains, being far superior to those of NVP and EFV. Moreover, <b>ZA-2</b> was demonstrated with lower cytotoxicity (CC₅₀ = 125 µM). In the reverse transcriptase inhibitory assay, <b>ZA-2</b> exhibited an IC₅₀ value of 0.057 µM with the ELISA method, and the MALDI-TOF MS data demonstrated the covalent binding mode of <b>ZA-2</b> with the enzyme. Additionally, the molecular simulations have also demonstrated that compounds can form covalent binding to the Tyr318.

The unique features of purine salvage systems of pathogenic haemoflagellates render them selectively susceptible to the cytotoxic effects of purine analogues. A series of acyclic nucleoside phosphonates were evaluated for activity against pathogenic haemoflagellates in vitro. One of the phosphonylmethoxyalkylpurines, namely (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine [(S)-HPMPA], was active in vitro against bloodstream forms of Trypanosoma brucei rhodesiense, T. b. gambiense, multidrug-resistant T. b. brucei, T. congolense and T. evansi, but not against intracellular T. cruzi or Leishmania donovani. Cytotoxic effects against mammalian cells were observed at 4900-27 300-fold higher concentrations than those necessary to inhibit T. b. rhodesiense. (S)-HPMPA was able to eliminate T. b. rhodesiense and multidrug-resistant T. b. brucei in an acute rodent model with two administrations of 10 mg/kg each.

Laser power fluctuations can significantly reduce the device performances in various applications. High frequency fluctuations impact the signal-to-noise ratio, while slow variations can reduce the device repeatability or accuracy. Here we report experimental investigations on the power stabilization of a diode laser with an acousto-optic modulator. In the frequency domain, the relative power noise is reduced at the level of 2.2 × 10^-8 Hz^-1/2 in the range 1-100 kHz. The slow variations are studied in the time domain. The relative Allan standard deviation is measured at the level of 6 × 10^-7 at 100 s averaging time. Above 100 s, the instability increases and reaches 2 × 10^-6 at 10 000 s.

Sonogashira coupling of (E)-6'-iodohomovinyl nucleosides 1 with (trimethylsilyl)acetylene gave the conjugated 8'-(trimethylsilyl)enyne derivatives of the adenosine 2a and uridine 2b with expected E-stereochemistry. Desilylation of 2a,b with tetrabutylammonium fluoride followed by treatment with N-iodosuccinimide/AgNO(3) afforded 8'-iodoenynes 4a,b. Analogous coupling of (Z)-6'-iodohomovinyl nucleosides 7a,b produced (Z)-8'-(trimethylsilyl)enynes 8a,b, which were deprotected with aqueous trifluoroacetic acid to give the Z-enynes 9a,b. Stereoselective coupling of the adenosine 4'-acetylenic 11 and ethyl (Z)-3-bromoacrylate followed by deprotection gave the conjugated enyne system attached in the reverse orientation at C4' 13. Because of their diverse stereochemical attributes, deprotected enyne analogues 5a, 6a, 9a, and 13 derived from adenosine require a different vicinity for binding with S-adenosyl-l-homocysteine (AdoHcy) hydrolase and/or addition of enzyme-bound water across the conjugated enyne system. Enyne 5a and 8'-iodoenyne 6a produced time-dependent and concentration-dependent inhibition of AdoHcy hydrolase (K(i), 0.55 and 118.5 microM, respectively). No reduction in NAD(+) content of the enzyme and no iodide ion released were observed upon incubation of 6a with the enzyme, while incubation of 5a produced 30% reduction in the NAD(+) content of the enzyme. No specific antiviral activity was noted for 5a,b, 6a,b, 9a,b, and 13 against any of the viruses tested; the E-iodoenynes 6a and 6b inhibited HIV-1 virus (IC(50), 1.1 and 1.8 microM; selectivity index, 7 and 3, respectively). The E-enyne 5a showed activity against cytomegalovirus at a concentration (EC(50), 30 microM) that was 3- to 10-fold lower than the cytotoxic concentration.

Genital condylomata acuminata are nonmalignant human papillomavirus (HPV)-induced tumors in which HPV types 6 and 11 are most commonly found. Usual treatments for condylomata acuminata are nonspecific and are based on the destruction or removal of infected tissue. These procedures are often painful and are characterized by a high relapse rate. We report here what is to our knowledge the first double-blind, placebo-controlled study of the use of cidofovir, a nucleotide analogue, for the treatment of genital papillomavirus infections. Thirty patients were enrolled in the study; 19 received cidofovir, and 11 received placebo. The median number of warts and the median baseline wart area were comparable for both groups. Nine (47%) of 19 patients in the cidofovir group had a complete response (total healing), compared with 0 of the patients in the placebo group (P=.006). None of the patients in the cidofovir group experienced progression of the disease, compared with 5 (45%) of 11 patients in the placebo group. The side effects recorded for both groups were comparable.

In laser powder bed fusion (LPBF), defects such as pores or cracks can seriously affect the final part quality and lifetime. Keyhole porosity, being one type of porosity defects in LPBF, results from excessive energy density which may be due to changes in process parameters (laser power and scan speed) and/or result from the part’s geometry and/or hatching strategies. To study the possible occurrence of keyhole pores, experimental work as well as simulations were carried out for optimum and high volumetric energy density conditions in Ti-6Al-4V grade 23. By decreasing the scanning speed from 1000 mm/s to 500 mm/s for a fixed laser power of 170 W, keyhole porosities are formed and later observed by X-ray computed tomography. Melt pool images are recorded in real-time during the LPBF process by using a high speed coaxial Near-Infrared (NIR) camera monitoring system. The recorded images are then pre-processed using a set of image processing steps to generate binary images. From the binary images, geometrical features of the melt pool and features that characterize the spatter particles formation and ejection from the melt pool are calculated. The experimental data clearly show spatter patterns in case of keyhole porosity formation at low scan speed. A correlation between the number of pores and the amount of spatter is observed. Besides the experimental work, a previously developed, high fidelity finite volume numerical model was used to simulate the melt pool dynamics with similar process parameters as in the experiment. Simulation results illustrate and confirm the keyhole porosity formation by decreasing laser scan speed.