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PubMed1991

Potent and selective inhibition of human immunodeficiency virus type 1 (HIV-1) by 5-ethyl-6-phenylthiouracil derivatives through their interaction with the HIV-1 reverse transcriptase.

In the search for 1-[(2-hydroxyethoxy)-methyl]-6-(phenylthio)thymine (HEPT) derivatives, we have found several 5-ethyl-6-(phenylthio)uracil analogues to be highly potent and selective inhibitors of human immunodeficiency virus (HIV) type 1. 1-Benzyloxymethyl-5-ethyl-6-phenylthiouracil, the most potent congener of the series, inhibits HIV-1 replication in a variety of cell systems, including peripheral blood lymphocytes, at a concentration of 1.5-7.0 nM, which is lower by a factor of 10(3) than the 50% antivirally effective concentration of the parent compound HEPT. The 5-ethyl-6-(phenylthio)uracil analogues, like HEPT itself, do not inhibit HIV-2 replication but do inhibit replication of 3'-azido-3'-deoxythymidine-resistant mutants of HIV-1. 1-Benzyloxy-methyl-5-ethyl-6-phenylthiouracil and its congeners are targeted at the HIV-1 reverse transcriptase (RT). They do not inhibit HIV-2 RT. They do not need to be metabolized to exert their inhibitory effect on HIV-1 RT. Yet this inhibitory effect is competitive with the natural substrate dTTP. The HEPT derivatives represent a group of RT inhibitors with a unique mode of interaction with HIV-1 RT.

Antiviral Agents↗
PubMed1992

A possible role for cysteine residues in the fidelity of DNA synthesis exhibited by the reverse transcriptases of human immunodeficiency viruses type 1 and type 2.

HIV reverse transcriptases (RTs) have few cysteine residues relative to other RTs and retain their DNA polymerization functions following chemical modification by thiol-specific reagents. The functional role of the cysteines in the fidelity of the DNA-dependent DNA synthesis of HIV RTs has been addressed by chemical modification of the wild-type enzymes in combination with the analysis of an enzymatically active mutant HIV-1 RT in which all cysteines were modified to serines. We have observed an increase in 3'-terminal mispair extension efficiency exhibited by chemically modified HIV-1 and HIV-2 RTs. The possible involvement of cysteine residues was further substantiated using the cysteine-free mutant HIV-1 RT that displays an increased efficiency of mispair extension. These results provide evidence for a possible role of cysteine residues in the fidelity of DNA synthesis catalyzed by HIV RTs.

Base Sequence↗
PubMed2000

Multidrug resistance genotypes (insertions in the beta3-beta4 finger subdomain and MDR mutations) of HIV-1 reverse transcriptase from extensively treated patients: incidence and association with other resistance mutations.

Multiple nucleoside resistance involves specific mutational patterns of the HIV-1 pol gene that are independent of the classic mutations conferring resistance to individual dideoxynucleosides. These include a cluster of five mutations in the reverse-transcriptase (RT) coding region (A62V, V75I, F77L, F116Y, and Q151M) generally referred to as multidrug resistance (MDR) mutations, and insertions of one or several amino acid residues between codons 67 and 70 of RT, a flexible region joining two antiparrallel beta sheets (beta3-beta4 insertions). The objectives of this study were (i) to determine the prevalence of multidrug resistance genotypes (MDR mutations and beta3-beta4 insertions) in a cohort of 632 patients who were extensively pretreated with anti-HIV drugs and not responding to their current antiretroviral therapy, and (ii) to analyze the association of multidrug resistance genotypes with other resistance mutations in the RT and protease genes. Among viruses sequenced from these patients, 15 (2.4%) of them contained an insertion and 2 (0.3%) contained a deletion in the beta3-beta4 finger subdomain of RT. In 9 cases, the insertion was associated with a D67S, G, or E mutation. In addition, we identified 13 (2.1%) viruses harboring specific MDR mutations (mainly Q151M and/or A62V, V75I, F116Y). Interestingly, the A62V mutation was found in 6 of the 15 strains with an insertion, whereas the other MDR mutations were not observed in insertion mutant strains. Especially high levels of resistance to zidovudine were observed for viruses with a beta3-beta4 insertion in the background of A62V, L210W, and T215Y. Otherwise, MDR mutations and beta3-beta4 insertions were found in association with the classic mutations conferring resistance to zidovudine, lamivudine, nonnucleoside RT inhibitors, and protease inhibitors, according to treatment history. Finally, we observed a genome with a deletion of codon 70 associated with a Q151M MDR mutation. These data suggest that the emergence of HIV-1 multidrug resistance, which may occur in various genetic contexts, poses a challenging problem in formulating treatment strategies.

Acquired Immunodeficiency Syndrome↗
PubMed1990

HIV-1 reverse transcriptase: structure predictions for the polymerase domain.

Reverse transcriptase (RT) plays an essential role in the life cycle of the human immunodeficiency viruses (HIV). A better understanding of this enzyme, and its two catalytic functions, the DNA polymerase and the RNase H, could lead to the development of new drugs that would specifically block HIV replication. The available genetic, sequence, biochemical, and immunological data on the reverse transcriptase of HIV-1 constrain the possible structure of the DNA polymerase domain. The purpose of this review is to correlate the data and to discuss, in light of that data, a model for the structure of the polymerase domain. In this model, the polymerase domain is approximately 50 to 60 A in diameter with a 20 A opening to accommodate the nucleic acid duplex. The most evolutionarily conserved region of RT (amino acids 20-190 of HIV-1 RT) is proposed to form the inner surface of the 20 A opening to which the nucleic acid hemiduplex is bound.

Amino Acid Sequence↗
PubMed1999

Lethal mutagenesis of HIV with mutagenic nucleoside analogs.

The human immunodeficiency virus (HIV) replicates its genome and mutates at exceptionally high rates. As a result, the virus is able to evade immunological and chemical antiviral agents. We tested the hypothesis that a further increase in the mutation rate by promutagenic nucleoside analogs would abolish viral replication. We evaluated deoxynucleoside analogs for lack of toxicity to human cells, incorporation by HIV reverse transcriptase, resistance to repair when incorporated into the DNA strand of an RNA.DNA hybrid, and mispairing at high frequency. Among the candidates tested, 5-hydroxydeoxycytidine (5-OH-dC) fulfilled these criteria. In seven of nine experiments, the presence of this analog resulted in the loss of viral replicative potential after 9-24 sequential passages of HIV in human CEM cells. In contrast, loss of viral replication was not observed in 28 control cultures passaged in the absence of the nucleoside analog, nor with other analogs tested. Sequence analysis of a portion of the HIV reverse transcriptase gene demonstrated a disproportionate increase in G --> A substitutions, mutations predicted to result from misincorporation of 5-OH-dC into the cDNA during reverse transcription. Thus, "lethal mutagenesis" driven by the class of deoxynucleoside analogs represented by 5-OH-dC could provide a new approach to treating HIV infections and, potentially, other viral infections.

Antimetabolites↗
PubMed2005

Nucleotide specificity of HIV-1 reverse transcriptases with amino acid substitutions affecting Ala-114.

Ala-114, together with Asp-113, Tyr-115 and Gln-151, form the pocket that accommodates the 3'-OH of the incoming dNTP in the HIV-1 RT (reverse transcriptase). Four mutant RTs having serine, glycine, threonine or valine instead of Ala-114 were obtained by site-directed mutagenesis. While mutants A114S and A114G retained significant DNA polymerase activity, A114T and A114V showed very low catalytic efficiency in nucleotide incorporation assays, due to their high apparent K(m) values for dNTP. Discrimination between AZTTP (3'-azido-3'-deoxythymidine triphosphate) and dTTP was not significantly affected by mutations A114S and A114G in assays carried out with heteropolymeric template/primers. However, both mutants showed decreased susceptibility to AZTTP when poly(rA)/(dT)16 was used as substrate. Steady-state kinetic analysis of the incorporation of ddNTPs compared with dNTPs showed that substituting glycine for Ala-114 produced a 5-6-fold increase in the RT's ability to discriminate against ddNTPs (including the physiologically relevant metabolites of zalcitabine and didanosine), a result that was confirmed in primer-extension assays. In contrast, A114S and A114V showed wild-type ddNTP/dNTP discrimination efficiencies. Discrimination against ribonucleotides was not affected by mutations at position 114. Misinsertion and mispair extension fidelity assays as well as determinations of G-->A mutation frequencies using a lacZ complementation assay showed that, unlike Tyr-115 or Gln-151 mutants, the fidelity of HIV-1 RT was not largely affected by substitutions of Ala-114. The role of the side-chain of Ala-114 in ddNTP/dNTP discrimination appears to be determined by its participation in van der Waals interactions with the ribose moiety of the incoming nucleotide.

Alanine↗
PubMed2003

Probing the mechanistic consequences of 5-fluorine substitution on cytidine nucleotide analogue incorporation by HIV-1 reverse transcriptase.

Beta-D and beta-L-enantiomers of 2',3'-dideoxycytidine analogues are potent chain-terminators and antimetabolites for viral and cellular replication. Seemingly small modifications markedly alter their antiviral and toxicity patterns. This review discusses previously published and recently obtained data on the effects of 5- and 2'-fluorine substitution on the pre-steady state incorporation of 2'-deoxycytidine-5'-monophosphate analogues by HIV-1 reverse transcriptase (RT) in light of their biological activity. The addition of fluorine at the 5-position of the pyrimidine ring altered the kinetic parameters for all nucleotides tested. Only the 5-fluorine substitution of the clinically relevant nucleosides (-)-beta-L-2',3'-dideoxy-3'-thia-5-fluorocytidine (L-FTC, Emtriva), and (+)-beta-D-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine (D-D4FC, Reverset), caused a higher overall efficiency of nucleotide incorporation during both DNA- and RNA-directed synthesis. Enhanced incorporation by RT may in part explain the potency of these nucleosides against HIV-1. In other cases, a lack of correlation between RT incorporation in enzymatic assays and antiviral activity in cell culture illustrates the importance of other cellular factors in defining antiviral potency. The substitution of fluorine at the 2' position of the deoxyribose ring negatively affects incorporation by RT indicating the steric gate of RT can detect electrostatic perturbations. Intriguing results pertaining to drug resistance have led to a better understanding of HIV-1 RT resistance mechanisms. These insights serve as a basis for understanding the mechanism of action for nucleoside analogues and, coupled with studies on other key enzymes, may lead to the more effective use of fluorine to enhance the potency and selectivity of antiviral agents.

Antiviral Agents↗
PubMed1993

Selective action of 4'-azidothymidine triphosphate on reverse transcriptase of human immunodeficiency virus type 1 and human DNA polymerases alpha and beta.

4'-Azidothymidine (ADRT) is a novel nucleoside analogue that exhibits potent inhibitory activity against the replication of human immunodeficiency virus (HIV) in lymphocytes. The mechanisms by which ADRT inhibits HIV reverse transcriptase (HIV-RT) as ADRT 5'-triphosphate (ADRT-TP), the active intracellular metabolite of ADRT, and as the ADRT-MP molecule incorporated into DNA were examined and compared to their effects on human DNA polymerases alpha and beta. Inhibition of HIV-RT by ADRT-TP is competitive against TTP and is more potent against RNA to DNA synthesis (Ki = 0.009 microM versus Km = 3.3 microM for TTP) than it is against DNA to DNA synthesis (Ki = 0.95 microM versus Km = 16.3 microM for TTP). ADRT-TP is also a more potent inhibitor for primer elongation on RNA template than on DNA template. ADRT-TP is a poor inhibitor of human DNA polymerases alpha (Ki = 62.5 microM) and beta (Ki = 150 microM) (Chen et al., 1992). The consequences of ADRT incorporation into DNA are strikingly different for the HIV-RT and for human DNA polymerases alpha and beta. DNA polymerases alpha and beta incorporate a single ADRT-MP molecule into nascent DNA at a very slow rate and continue to elongate. They are unable to incorporate a second consecutive ADRT-MP. However, HIV-RT is able to efficiently incorporate two consecutive ADRT molecules. Incorporation of two consecutive ADRT-MP molecules by HIV-RT prevents further DNA chain elongation. Incorporation of two ADRT-MP molecules separated by one deoxyribonucleoside monophosphate (dAMP, dCMP, or dGMP) also abolishes DNA chain elongation by HIV-RT.

Antiviral Agents↗
PubMed1999

The effect of template RNA structure on elongation by HIV-1 reverse transcriptase.

Reverse transcription of the RNA genome of retroviruses has to proceed through some highly structured regions of the template. The RNA genome of the human immunodeficiency virus type 1 (HIV-1) contains two hairpin structures within the repeat (R) region at the 5' end of the viral RNA (Fig. 1Fig. 1Template RNA structure of the HIV-1 R region and the position of reverse transcription pause sites. The HIV-1 R region (nucleotides +1/97) encodes two stable RNA structures, the TAR and polyA hairpins [5]. The latter hairpin contains the AAUAAA hexamer motif (marked by a box) that is involved in polyadenylation. The lower panel shows the predicted structures of the wild-type and two mutant forms of the polyA hairpin that were used in this study. Nucleotide substitutions are boxed, deletions are indicated by black triangle. The thermodynamic stability (free energy or DeltaG, in kcal/mol) was calculated according to the Zucker algorithm [71]. The TAR hairpin has a DeltaG of -24.8 kcal/mol. Minus-strand DNA synthesis on these templates was initiated by a DNA primer annealed to the downstream PBS. The position of reverse transcription pause sites observed in this study are summarized. All numbers refer to nucleotide positions on the wild-type HIV-1 transcript. Filled arrows represent stops observed on the wild-type template, and open arrows mark the pause sites that are specific for the structured A-mutant template. The sizes of the arrows correspond to the relative frequency of pausing. Little pausing was observed on the B-mutant template with the destabilized polyA hairpin.). These structures, the TAR and polyA hairpins, fulfil important functions in the viral life cycle. We analyzed the in vitro elongation properties of the HIV-1 reverse transcriptase (RT) enzyme on the wild-type RNA template and mutants thereof with either a stabilized or a destabilized polyA hairpin. Stable RNA structure was found to interfere with efficient elongation of the RT enzyme, as judged by the appearance of pause cDNA products. A direct relation was measured between the stability of template RNA structure and the extent of RT pausing. However, the position of structure-induced pause sites is rather diverse, with significant stops at a position approximately 6 nt ahead of the basepaired stem of the TAR and polyA hairpins. This suggests that the RT enzyme is stalled when its most forward domain contacts the RNA duplex. Addition of the viral nucleocapsid protein (NC) to the in vitro assay was found to overcome such structure-induced RT stops. These results indicate that the RT polymerase has problems penetrating regions of the template with stable RNA structure. This effect was more pronounced at high Mg2+ concentrations, which is known to stabilize RNA secondary structure. Such a structure-induced defect was not apparent in reverse transcription assays performed in virus-infected cells, which is either caused by the NC protein or other components of the virion particle. Thus, retroviruses can use relatively stable RNA structures to control different steps in the viral life cycle without interfering with the process of reverse transcription.

Base Sequence↗
PubMed2000

Novel 1,5-diphenylpyrazole nonnucleoside HIV-1 reverse transcriptase inhibitors with enhanced activity versus the delavirdine-resistant P236L mutant: lead identification and SAR of 3- and 4-substituted derivatives.

Through computationally directed broad screening, a novel 1, 5-diphenylpyrazole (DPP) class of HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs) has been discovered. Compound 2 (PNU-32945) was found to have good activity versus wild-type (IC(50) = 2.3 microM) and delavirdine-resistant P236L (IC(50) = 1.1 microM) reverse transcriptase (RT). Also, PNU-32945 has an ED(50) for inhibition of viral replication in cell cultures of 0.1 microM and was shown to be noncytotoxic with a CC(50) > 10 microM. Structure-activity relationship studies on the 3- and 4-positions of PNU-32945 led to interesting selectivity and activity within the class. In particular, the 3-hydroxyethyl-4-ethyl congener 29 is a potent inhibitor of the P236L mutant (IC(50) = 0.65 microM), whereas it is essentially inactive versus the wild-type enzyme (IC(50) > 50 microM). Furthermore, this compound was significantly more active versus the P236L mutant than delavirdine. The synthesis and RT inhibitory activity of various 3- and 4-substituted analogues are discussed.

Anti-HIV Agents↗
PubMed1993

Human immunodeficiency virus reverse transcriptase. Expression in Escherichia coli, purification, and characterization of a functionally and structurally asymmetric dimeric polymerase.

Human immunodeficiency virus (HIV) reverse transcriptase isolated from viral particles contains two subunits, p51 and p66. We have produced both subunits in separate Escherichia coli strains using expression vectors. Stop codons were placed immediately after the codon for the carboxyl-terminal residue of the mature processed p51 and p66 subunits found in viral particles. Insertion of a methionine in front of the HIV protease cleavage site in the recombinant protein enabled synthesis of both subunits with the natural amino-terminal proline, since E. coli methionine aminopeptidase cleaves a Met-Pro amino-terminal linkage. That this occurred to an extent greater than 95% was confirmed by sequencing the purified subunits. Examination of the activities of the individual p51 and p66 subunits on a variety of templates and under solution conditions optimized for each subunit revealed a significant catalytic activity for the natural p51 subunit. This result contrasts to results reported earlier for many recombinant forms without the natural amino and/or carboxyl termini. As expected from earlier work, the optimal homopolymeric template for the p66 subunit was poly(rA). For the p51 subunit, poly(dC) was found to be the optimal template; its activity is 2- to 4-fold greater than p66 on poly(dC). The p51 subunit is 13- to 50-fold less active on poly(rC). These findings are discussed in the context of our earlier hypothesis (McHenry, C. S. (1989) in Molecular Biology of Chromosome Function (Adolph, K., ed) Chap. 5, Springer-Verlag, New York) that the HIV reverse transcriptase might be functionally asymmetric with distinct plus- and minus-strand polymerases.

Base Sequence↗
PubMed2005

Fixed conformation nucleoside analogs effectively inhibit excision-proficient HIV-1 reverse transcriptases.

An important mechanism of resistance to nucleoside analogs is the enhanced excision of the analog after it has been incorporated. Excision requires that the analog be located at the 3' terminus of the primer. We have developed nucleoside analogs that do not block DNA synthesis at the point of incorporation, but only after additional normal dNTPs have been added to the DNA. Such "delayed chain terminators" should be relatively resistant to excision and therefore effective against drug-resistant HIV-1 reverse transcriptases (RTs) that are proficient at excision. We tested a class of nucleoside analogs in which a pseudosugar ring is locked in either the North or the South conformation. These analogs have a 3' OH present on the pseudosugar ring, which allows extension of the primer strand after the analog is incorporated. We asked whether these analogs would inhibit polymerization by HIV-1 RT in assays using purified HIV-1 RT and in cell-based assays. HIV-1 RT did not effectively incorporate the analogs in which the pseudosugar is in the South conformation. The North conformation analogs are readily incorporated into the primer; the primer can be extended for two or three additional nucleotides before extension is inhibited. This block to polymerization is not complete; larger extension products are detectable at longer incubation times. Experiments with purified excision-proficient HIV-1 RT mutants suggest that the North conformation analogs are relatively resistant to excision. These analogs can also block the replication of viruses containing excision-proficient RTs. Although the fixed-conformation nucleotides are probably not suitable for development as drugs, other nucleoside analogs that cause delayed chain termination may complement the nucleoside analogs already approved for HIV-1 therapy.

Base Sequence↗
PubMed1999

Resistance to non-nucleoside inhibitors of HIV-1 reverse transcriptase.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are a structurally diverse group of compounds which function as inhibitors of HIV-1 replication in vitro and in vivo. Viral resistance is mediated through alterations in the amino acids which form the allosteric site on the HIV-1 reverse transcriptase to which NNRTIs bind. The rapid emergence of resistant viruses has limited the utility of NNRTI monotherapy; however, recent clinical studies have shown that potent NNRTIs can contribute to profound suppression of HIV replication when used in combination therapy. An understanding of the development of resistance to NNRTIs is critical to the effective use of this class of antiretroviral agents. Copyright 1999 Harcourt Publishers Ltd.

Journal Article↗
PubMedDate not supplied

Fast genotypic detection of drug resistance mutations in the HIV-1 reverse transcriptase gene of treatment-naive patients.

OBJECTIVES: This study was performed to assess the frequency of drug resistance mutations in treatment-naive HIV-1-infected patients. STUDY DESIGN/METHODS: Frozen plasma samples from 135 treatment-naive HIV-infected adults were available from the first time the patients were seen for their infection in our center between 1992 and 1997. A rapid genotypic assay based on reverse DNA hybridization (LiPA HIV-1 RT, Murex, London, U.K.) was used to study substitutions at reverse transcriptase (RT) codons 41, 69, 70, 74, 184, and 215. Additionally, a selective polymerase chain reaction (PCR) for the multiple dideoxynucleoside resistance (MddNR) mutation Q151M was performed. RESULTS: 16 patients (12%) harbored virus with one or more drug resistance mutations. The prevalence of patients with drug-resistant virus was 0% in 1992, 17% in 1993, 0% in 1994 (only 6 samples tested), 18% in 1995, 14% in 1996, and 9% in 1997. Mutation K70R (resistance to zidovudine) was found in 8 patients, M41L (resistance to zidovudine) in 5 patients, M184V/I (resistance to ddI/ddC/3TC) in 2 patients, and T215Y/F (resistance to zidovudine) in 4 patients. All samples were wild type at codons 69 (ddC), 74 (ddI), and 151 (MddNR). CONCLUSIONS: Virus strains containing drug resistance mutations are now found in about 1 of 10 treatment-naive HIV-1-seropositive patients in Luxembourg. We believe that testing for drug-resistant virus before starting treatment should be recommended and will help to improve the selection of the most effective antiretroviral treatment. We also suggest the need for an international surveillance program on HIV drug resistance in treatment-naive patients.

Adult↗
PubMed2001

Low-rate emergence of thymidine analogue mutations and multi-drug resistance mutations in the HIV-1 reverse transcriptase gene in therapy-naive patients receiving stavudine plus lamivudine combination therapy.

OBJECTIVES: Mutations usually associated with zidovudine exposure have been observed in zidovudine-naive patients treated by stavudine in combination. These mutations were named thymidine analogue mutations (TAMs). This fact, combined with phenotypical and biochemical findings provided additional evidence for cross-resistance between zidovudine and stavudine. A recent genotypic study in naive patients receiving stavudine/didanosine combination showed emergence of TAMs and a multidrug-resistance mutation (MDR), Q151M, in 36 and 10% of cases, respectively. Stavudine plus lamivudine is one of the most used binucleoside associations in the antiretroviral combinations. The objective of this study was to assess the genotypic changes in the HIV-1 reverse transcriptase (RT) gene in antiretroviral-naive patients treated by stavudine plus lamivudine. METHODS: We analysed the RT gene of 44 HIV-1 patients, naive of antiretroviral therapy, who were treated for 24 or 48 weeks with stavudine/lamivudine. RESULTS: At the end of the follow-up, all patients acquired the lamivudine-associated mutation M184V. Only two subjects (4.5%) developed a TAM (T215Y; M41L), one subject developed a V75T/A mutation and one subject developed the particular MDR pattern F116Y, Q151M. CONCLUSIONS: Our study clearly demonstrated that naive subjects treated with stavudine/lamivudine for 24-48 weeks selected a low rate of TAMs and MDR Q151M. One hypothesis explaining these results could be the development of the M184V mutation.

Acquired Immunodeficiency Syndrome↗
PubMed1996

[Zidovudine-resistant HIV strains in intravenous drug users and homosexual men in Amsterdam].

OBJECTIVE: To investigate the spread of HIV strains resistant to antiviral drugs prescribed in the Netherlands. DESIGN: Descriptive. SETTING: Amsterdam. METHOD: In several cohorts of homosexual men and intravenous drug users being followed in Amsterdam, in cases of newly acquired HIV infections in the period 1992-1995 HIV RNA was isolated from serum. The nucleic acid sequence encoding the first 250 amino acids of the HIV reverse transcriptase was determined in order to detect mutations conferring resistance to reverse transcriptase inhibitors. RESULTS: Among participants of the Amsterdam cohort studies, 12 new HIV infections of homosexual men and 23 of IV drug users were observed. In the group of homosexual men the first infection by a zidovudine-resistant HIV was observed in 1995. In the group of IV drug users the first infection by a zidovudine-resistant strain was noticed in 1993 with two more infections in 1995. The mutations regarded positions 41, 67, 70 and 215 of the HIV reverse transcriptase. No HIV strains resistant to didanosine, deoxycytidine, lamuvidine or nevirapine were found in untreated persons with an acute infection. CONCLUSION: As zidovudine is a vital part of the latest and most efficacious combination therapies of HIV infection, testing for zidovudine-resistance prior to treatment is recommended.

Cohort Studies↗
PubMed2004

Coccinin, an antifungal peptide with antiproliferative and HIV-1 reverse transcriptase inhibitory activities from large scarlet runner beans.

An antifungal peptide, designated coccinin, with a molecular mass of 7kDa and an N-terminal sequence resembling those of defensins, was purified from the seeds of large scarlet runner beans (Phaseolus coccineus cv. 'Major'). The peptide isolated was unadsorbed on DEAE-cellulose, and adsorbed on Affi-gel blue gel and Mono S. The peptide excerted antifungal activity on a number of fungal species including Botrytis cinerea, Coprinus comatus, Fusarium oxysporum, Mycosphaerella arachidicola, Physalospora piricola, and Rhizoctonia solani. It also inhibited proliferation in the leukemia cell lines HL60 and L1210, and reduced the activity of HIV-1 reverse transcriptase. However, it did not affect proliferation of mouse splenocytes.

Amino Acid Sequence↗